Abstract

Purpose: A sedentary lifestyle is associated with an increased likelihood of developing diabetes mellitus. However, regular physical activity helps regulate metabolism, which may help prevent several long-term health issues.

Methods: Diabetic kidney disease is the most prevalent microvascular complication of diabetes mellitus and increases the risk of death from cardiovascular disease in individuals with diabetes. The primary pathophysiological mechanisms leading to tissue damage, extracellular matrix formation, and reduced renal function are oxidative stress, renal inflammation, and activation of the renin-angiotensin-aldosterone system.

Results: Although exercise has proven beneficial in cardiovascular disease, there is a lack of understanding of how it affects the pathophysiological processes that lead to diabetic kidney disease. Moreover, there is a scarcity of physical rehabilitation programs and standardized experimental models for individuals with diabetic renal disease.

Conclusion: This review article provides a concise overview of the pathophysiological mechanisms of diabetic kidney disease and discusses its etiology. It then highlights recent research on the effects of exercise on the development of this disease.

Keywords:Chronic Kidney Disease; Diabetes Mellitus; Diabetic Nephropathy; Resistance; Training

Abbreviations:DKD: Diabetic Kidney Disease; CKD: Chronic Kidney Disease; ESKD: End-Stage Renal Disease; DM: Diabetes Mellitus; T1DM: Type 1 Diabetes Mellitus; T2DM: Type 2 Diabetic Mellitus; RAAS: Renin-Angiotensin-Aldosterone System; GFR: Glomerular Filtration Rates; Egfr: Estimated Glomerular Filtration Rate; AMPK: AMP-Activated Protein Kinase; PIKK: Akt/Phosphatidylinositol-3-Kinase/Protein Kinase B; MAPK: Mitogen-Activated Protein Kinase; ESRD: End-Stage Renal Disease; IRS: Insulin Receptor Substrate; GLUT4: Glucose Transporter 4; LKB1: Liver Kinase B1; mTOR: Mammalian Target of Rapamycin; HIIT: High-Intensity Interval Training; CaMKII: Calmodulin-Dependent Protein Kinase II; ROS: Reactive Oxygen Species; Sirt1: Silencing Information Regulator 1; NOS: Nitric Oxide Synthase; GEC: Glomerular Endothelial Cell; NO: Nitric Oxide; ECM: Extracellular Matrix; NF-κB: Nuclear Factor Kappa-B; PKC: Protein Kinase C; Nrf2: Nuclear Factor Erythroid-Related Factor 2; MDA: Malondialdehyde; GSH-Px: Glutathione Peroxidase; iNOS: Inducible Nitric Oxide Synthase; AngI: Angiotensin I; ACE: Angiotensin-Converting Enzyme; AngII: Angiotensin II; AT1R: Angtype II Receptor 1; TGF-β1: Transforming Growth Factor Beta-1; ND: non-disease; RCTs: Randomised Controlled Trials

Introduction

The worldwide escalation in type 2 diabetes mellitus is linked to a growing cardiovascular risk and significant health consequences [1]. Type 2 diabetes can lead to complications such as diabetic nephropathy, a disorder that affects the tiny blood arteries in the kidneys and causes urine protein loss [2]. This can result in kidney damage and a decline in their function [3]. The continuum of renal dysfunction spans from a slight to a severe reduction in nephron count [4]. Pharmacological interventions are the primary method used, although in severe situations, further interventions such as hemodialysis, peritoneal dialysis, kidney transplantation, or other renal replacement therapy may be required. The prevalence of diabetic kidney disease (DKD) in our country has surpassed 24 million individuals, which is attributable to the confluence of economic development and altered lifestyles. The projected expenses for DKD patients with accompanying conditions over the ensuing five years are estimated to reach 148 million [5]. Diabetes mellitus (DM) affects 463 million people globally, and 20% to 40% of DM patients may develop DKD, according to the American College of Sports Medicine [6]. Globally, DKD is not only the primary cause of chronic kidney disease (CKD) and end-stage renal disease (ESKD) but also functions as a distinct risk factor for cardiovascular disease. Furthermore, the incidence of cardiovascular and cerebrovascular diseases, as well as premature mortality, is 20 to 40 times greater in individuals with DKD than in those without DKD [7,8].

DM, a systemic metabolic disorder, can be classified into two types: type 1 diabetes mellitus (T1DM) and type 2 diabetic mellitus (T2DM). T2DM is more prevalent in the development of DM. In the context of T2DM, the disruption of renal metabolism and hemodynamics, as well as their interplay, contribute to the advancement of DKD [9]. The disruption of blood glucose management primarily characterizes the development of DKD, increased oxidative stress and inflammation in the kidneys, and dysregulation of the renin-angiotensin-aldosterone system (RAAS). Clinically, DKD results in glomerular hypertrophy, basement membrane thickening, mesangial hyperplasia, interstitial fibrosis, and other related changes. Current medication treatment of DKD can result in hypoglycemia, hypokalemia, and severe pancreatitis in certain DKD patients [10]. Exercising is a non-pharmaceutical intervention therapy that can improve DKD in many ways, including restoring glomerulus and basement membrane function, reducing interstitial fibrosis, and alleviating renal oxidative stress and inflammatory response (Figure 1). Even though their albuminuria levels are within the normal range, people with type 2 diabetes that begins in childhood, diabetic nephropathy (DN), DKD, or CKD have a higher risk of cardiovascular disease [11,12]. The heightened risks are contributed by metabolic compensation resulting from insufficient glycemic management, hypertension, and dyslipidemia in individuals with DKD/CKD [13,14].

Early screening is crucial, as around 7% of persons diagnosed with type 2 diabetes show signs of microalbuminuria, while 30% with normoalbuminuria experience reduced glomerular filtration rates (GFR) [15,16]. In addition to albuminuria and GFR, current guidelines include evaluating serum creatinine levels [17,18]. The increasing prevalence of diabetes and nephropathy is a significant problem for healthcare providers and carers [19,20]. The identified risk factors for DN and its progression include age, male gender, long duration of diabetes, estimated glomerular filtration rate (eGFR) > 90 mL/min/1.73 m2 (indicating early hyperfiltration), systolic blood pressure higher than 130 mm Hg, and chronic proteinuria with concurrent retinopathy [21,22]. These conditions have a negative effect on people’s physical abilities, general health, and quality of life. They can cause anemia, exhaustion, pain, dyspnea, sarcopenia, and frailty.

Patients with CKD typically exhibit a substantial decline in physical function, which can range from 50% to 80% compared to healthy individuals. This decrease can be attributed to proteinenergy waste, protein breakdown, and mitochondrial dysfunction [23,24]. DN is characterized by the activation of many molecular pathways due to chronic inflammation and hyperglycemia [25,26]. Physical activity and limiting calorie intake have shown promise in delaying the onset of kidney failure and fibrotic alterations [27]. The significance of rehabilitation in renal dysfunction has garnered attention, emphasizing the necessity for more studies to elucidate the renoprotective benefits of exercise. Preventive interventions, early detection, patient education, promotion of lifestyle adjustments, and the incorporation of exercise are critically necessary for patients with type 2 diabetes and nephropathy. This systematic review aims to investigate how exercise affects renal function in individuals with nephropathy and type diabetes mellitus.

Exploring Mechanisms Underlying the Positive Impact of Physical Activity on Chronic Kidney Disease

Organized exercise, even for a brief duration, induces various changes at many tissue levels that may help explain why it is effective in preventing the development or progression of renal disease (Figure 2). The mitigation of the pathophysiological manifestations of DKD is well established. Our objective was to enhance clinical exercise recommendations and heighten the practical relevance of our findings by identifying the types and durations of exercise that yield the most substantial health benefits for individuals with DKD. The beneficial effects of physical activity in the management of DKD are garnering increasing attention. This study concentrated on the potential of individualized exercise programs to operate as crucial supplementary treatments in this context. Our study aimed to evaluate the intricate role of exercise in mitigating the adverse consequences of DKD. Research has demonstrated that patients with DKD can significantly benefit from engaging in aerobic exercises, which enhance cardiovascular fitness and insulin sensitivity [10]. Regular moderate-to-vigorous aerobic activities, such as jogging, swimming, or cycling, can assist individuals with DKD in managing their condition by reducing their blood pressure and improving their glycaemic control. Additionally, resistance training has been found to be as effective as aerobic exercises in enhancing metabolic health and muscle strength.

Weight training and resistance band exercises are examples of this type of physical activity, which helps slow the progression of type 2 diabetes by increasing insulin sensitivity and improving glucose uptake in the muscles [28]. Although aerobic and resistance training are essential components of an exercise regimen for individuals with DKD, it is also recommended that they incorporate balance and flexibility routines for optimal health. Although these exercises may not have an immediate impact on DKD parameters, they play a crucial role in overall disease management, particularly in preventing falls and enhancing the quality of life of those suffering from it. It also emphasizes the significance of customizing exercise schedules and durations, considering each patient’s medical history and individual preferences. For patients with DKD, personalized exercise is crucial to maximize therapeutic benefits and ensure adherence. Comprehensive research has demonstrated the central role of exercise in treating DKD, highlighting the forms and quantities of physical activity that yield the most substantial benefits. This review aims to enhance the health outcomes and quality of life of patients with DKD by offering evidence-based, personalized exercise recommendations that cater to their unique requirements. This can be accomplished by refining and informing clinical practices.

Exercise Enhances Endothelial Performance

Physical exercise controls the manufacture of nitric oxide (NO) by increasing the bioavailability of the precursor of NO, L-arginine, and the activity of endothelial NO synthase [29,30]. In addition, engagement in physical activity contributes to the reduction of NO degradation by diminishing the presence of reactive oxygen species (ROS). NO is recognized as an essential paracrine modulator affecting multiple aspects of renal function, such as renal self-regulation, glomerular filtration, renin release [31], and salt excretion as shown that inadequate NO levels have been associated with the decline in renal health, including the exacerbation of ailments like glomerulosclerosis and tubulointerstitial inflammation with fibrosis [32,33].

Physical Exercise Improves Insulin Resistance

Regardless of weight loss, engaging in a single exercise session increases insulin sensitivity. More precisely, it aids in absorbing glucose in skeletal muscle without insulin and triggers the activation of AMP-activated protein kinase (AMPK). As a result, this activation causes the phosphorylation of TBC1D1, a crucial component in controlling intracellular membrane trafficking, which belongs to the Tre-2/BUB2/CDC 1 domain family. TBC1D1 is deactivated through phosphorylation, which facilitates the binding of GTP and Rab proteins on the GLUT4 vesicles. As a result, this process encourages the movement of GLUT4 vesicles from the cytosol to the cell membrane, increasing glucose absorption into the cell [34,35]. Hence, physical activity significantly improves glucose absorption by muscles, regardless of the presence of insulin. Insulin resistance is principally linked with reduced muscle phosphatidylinositol 3-kinase/Akt signaling in advanced renal disease, which may result in heightened catabolism, a restricted anabolic response, and muscle wasting [36,37]. Activating the AMPK Akt/phosphatidylinositol-3-kinase/protein kinase B (PIKK) pathway, insulin resistance leads to hyperinsulinemia even in the initial stages of renal disease. Activation in endothelial cells leads to a decrease in NO generation dependent on Akt and an increase in vasoreactivity dependent on mitogen-activated protein kinase (MAPK). This contributes to the destruction of microvessels [38]. The significance of insulin signaling at the podocyte level is particularly intriguing. Podocytes exhibit a notable ability to respond to insulin to facilitate the uptake and metabolism of glucose. Lab experiments have shown that when podocytes develop insulin resistance, albumin is produced in the urine. This is accompanied by a thickening of the glomerular basement membrane and the development of glomerulosclerosis [39,40]. Nevertheless, it is still unclear whether the enhancement in insulin sensitivity caused by exercise can result in improved podocyte insulin signaling.

Physical Activity Alters Adipose Tissue & Adipocytokines

Research indicates that visceral adipocytes generate several adipocytokines, such as resistin, ghrelin, leptin, TNF-α, plasminogen activator inhibitor-1, and angiotensinogen. These adipocytokines have been found to affect the development of endothelial damage in the kidney, which may contribute to the development of CKD [41]. Weight loss protects against the advancement of CKD [42]. Additionally, decreased levels of inflammation and ROS are linked to modified adipose tissue distribution, especially loss of visceral adiposity. This could lead to better results for the kidneys [43].

Exercises against Diabetic Kidney Disease

Progressive renal failure is a common complication of diabetes in patients who also have proteinuria. Hence, it is of great clinical interest to determine whether physical exercise can slow the progression of renal disease in this population. Although aerobic training has been proven to slow the evolution of nephropathy in rats with type 1 diabetes in animal models [44], there is still a lack of information regarding the effects of exercise on diabetic patients derived from intervention trials. Immediate albuminuria is worsened in individuals with type 2 diabetes who engage in vigorous exercise [45]. Following intense exercise, there is an increase in the levels of Angiotensin-2, which leads to an increase in glomerular membrane permeability. Consequently, the urinary albumin excretion rate also increased. Furthermore, tubular proteinuria may occur when lactic acid generated during exercise enters the tubular lumen and impairs the ability of the proximal tubule to reabsorb proteins [46]. The current state of research on the effects of exercise on nephropathy in individuals with type 1 diabetes lacks extensive randomized controlled studies. In the first study to examine the impact of exercise on microvascular complications in type 1 diabetes, researchers in Pittsburgh discovered that males with higher levels of physical activity both now and when they were adolescents had a lower risk of developing DN and neuropathy. However, this correlation was not observed in women. Additionally, compared with normoalbuminuric patients, microalbuminuric individuals in the FinnDiane cross-sectional survey were less active, which is an intriguing finding [47].

Two large cohorts have provided prospective data on the impact of exercise on nephropathy. Despite the lack of a correlation between exercise and the development of nephropathy, the DCCT cohort, which included patients with newly diagnosed type 1 diabetes, suggested that exercise should be promoted as part of managing type 1 diabetes [48]. Thus, to determine risk factors for DN and other consequences, the FinnDiane study included individuals with type 1 diabetes at different phases of the disease. Over a mean follow-up time of 6.4 ± 3.1 years, 1424 patients with a diabetes duration exceeding 20 years were monitored for changes in albumin excretion rate or the onset of ESKD in a study that examined the impact of exercise on DN [49]. This study represents the first attempt to investigate the relationship between physical activity and DN. Notably, research has revealed that exercise intensity, as opposed to quantity, plays a crucial role in this connection. It was discovered that the higher the intensity, the lower the chances of developing or worsening DN. Surprisingly, this correlation persisted regardless of smoking status, age at diabetes onset, sex, or duration of diabetes. Although the association weakened after adjusting for variables such as triacylglycerol, blood pressure, HbA1c, and body mass index, it remained significant. The study’s longitudinal design allows for the possibility of reverse causality. Recent Mendelian randomization data from three large case-control cohorts suggest that obesity is a causative factor in DKD [50]. Consequently, exercise may slow the development of DKD by reducing the prevalence of obesity.

Exercise and Blood Glucose Homeostasis

Hyperglycaemia, a hallmark of type 2 diabetes, arises gradually from factors such as insulin resistance, diminished insulin secretion, and aberrant glucagon metabolism. Moreover, sustained high blood sugar levels within the body ultimately result in DKD [51]. The insulin receptor substrate (IRS) is crucial in transmitting insulin signals and facilitating glucose absorption by skeletal muscle [52]. Previous research has demonstrated that mice lacking IRS1 exhibit peripheral insulin resistance and delayed growth and development; animals lacking IRS2 exhibit metabolic abnormalities in the liver, skeletal muscle, and fat in addition to pancreatic β cell death [53]. Simultaneously, activation of AMPK, a sensor for energy metabolism, also facilitates glucose transporter 4 (GLUT4) in skeletal muscle. GLUT4 protein translocates from intracellular cisterns to cell membranes, facilitating glucose transport from the bloodstream into cells [54]. However, it has been noted that amidst high glucose levels, AMPK and liver kinase B1 (LKB1) undergo dissociation [55]. Furthermore, another study highlighted that the activation of the mammalian target of rapamycin (mTOR) could impede the insulin signal mediated by S6K1 in the skeletal muscle of obese mice who were fed a highfat diet [56]. IRS1 and IRS2 undergo degradation, leading to diminished glucose absorption and glycogen buildup in skeletal muscle. Additionally, an elevated level of S6K1 phosphorylation in the skeletal muscle of patients with T2DM was observed [57]. Therefore, IRS1 and IRS2 are crucial in maintaining appropriate blood glucose levels, while AMPK protein levels decrease and its signaling pathway is obstructed in conditions of elevated glucose. Conversely, the expression of the mTOR protein is heightened, resulting in the activation of its signaling pathway.

The examination of the relationship between exercise intensity and the advancement of DKD is of paramount importance for the development of more effective therapeutic strategies for this condition. It is crucial to possess a comprehensive understanding of the precise impacts of varying exercise intensities on the progression of DKD in order to develop tailored exercise plans that patients can adhere to at different stages of the disease [58]. The correlation between exercise intensity and its favorable effects on DKD is not strictly linear. A recent study has suggested that moderate-intensity exercise is preferable due to its cardiovascular and metabolic benefits [59]. Such exercises involve a level of exertion that is both achievable and challenging, and they often aid in improving glucose control and regulating blood pressure, which are critical factors in managing DKD. However, it is essential to thoroughly investigate the potential influence and efficacy of high-intensity interval training (HIIT) in this particular group. HIIT, characterized by short bursts of strenuous exercise alternating with rest periods or low-intensity exercise, may offer distinct advantages, including enhanced cardiovascular fitness and insulin sensitivity. This is particularly advantageous for individuals with DKD. It is vital to take into account the impact of exercise intensity while simultaneously prioritizing patient safety and ensuring the exercise routine can be sustained in the long run. While intense exercises may offer specific advantages, they may only be suitable for certain patients, particularly those with advanced stages of DKD or other medical conditions. Therefore, it is essential to conduct a comprehensive evaluation to determine the most appropriate intensity level based on the patient’s clinical condition, abilities, and personal preferences. This discussion encompasses the adaptation of workout routines, with a focus on the varying characteristics of DKD and its progression. Patients in the early stages of DKD may derive significant benefits from exercise regimens that differ from those with advanced disease. This underscores the need for a flexible and adaptable approach when prescribing exercises. This adaptive approach should not only consider the disease stage but also incorporate other individual factors, such as age, comorbidities, and overall physical condition.

The Exercise-Glucose Connection

Research on glucose homeostasis revealed that a 10-week program of aerobic exercise led to an increase in IRS1 protein expression in insulin-resistant rats. Moreover, PI3-K, a protein highly associated with IRS1, is more active in human skeletal muscle during intermittent aerobic activity [60]. Furthermore, it enhances the glucose absorption by GLUT4 in skeletal muscle [61]. Another study showed that moderate-intensity aerobic exercise in rats with DM resulted in higher levels of IRS2 protein content, GLUT4 protein content, and IRS2 phosphorylation [62]. Furthermore, the growing impact of GLUT4 protein content and IRS2 phosphorylation persisted for 48 hours. Meanwhile, through IRS1/PI3-K/AKT/GLUT4, aerobic exercise can alleviate insulin resistance [63]. Hence, physical activity can enhance peripheral insulin resistance by activating the IRS1/PI3-K/AKT/GLUT4 pathway. Aerobic exercise might raise the levels of LKB1 and AMPK proteins in rats but had no discernible effect on the LKB1/ AMPK signal in the islet beta cells of insulin-resistant rats [64]. Exercise activates AMPK and its preceding complex, UNC51-like kinase 1, ULK1. Activated ULK1 can enhance islet beta cell activity by phosphorylating autophagy proteins ATG13 and FIP200 [65]. Furthermore, resistance training with a 70% to 80% load was performed on DKD patients, and the patient’s blood glucose, glycated hemoglobin, and blood creatinine levels considerably dropped [66]. Hence, physical activity enhances the production of LKB1 and AMPK and maintains blood glucose levels by regulating the autophagy process in islet beta cells.

Exercise Boosts Bone-Related Blood Glucose Control

The role of calcium concentration and the number of calmodulin complexes in muscle contraction is well established. Calmodulin-dependent protein kinase II (CaMKII) is a critical component of the calcium-dependent calmodulin signaling pathway and plays a vital role in enabling skeletal muscles to take up glucose [67]. Meanwhile, It was observed that inhibiting the expression of the CaMKII gene in skeletal muscle resulted in a 35% decrease in CaMK activity and a 30% decrease in glucose intake [68]. However, the amount of GLUT4 protein remained the same, and there was a considerable increase in the degree of AMPK phosphorylationAnother research showed that aerobic exercise could potentially enhance the level of perinuclear phosphorylation of CaMKII in skeletal muscle [69]. Additionally, they observed a 2.2-fold rise in GLUT4 mRNA content and a 1.8- fold increase in protein content of CaMKII. At the same time, it was verified that compared to resting time, AMPK and CaMKII phosphorylation in healthy volunteers’ lateral femur muscles rose 2.9 and 2.7 times, respectively, following HIIT [70]. There was no rise in AMPK and CaMKII phosphorylation levels after 3 hours. Hence, achieving a specific intensity level during exercise is imperative to stimulate CaMKII effectively. Additionally, there may be some overlap between CaMKII and AMPK in their regulation of the mechanism responsible for maintaining blood glucose levels in the body.

Exercise Optimizes mTOR for Glucose Homeostasis

Inhibition of the mTOR pathway can result in a reduction in the body’s susceptibility to inflammation, proliferation, and autophagy activation. This is because mTOR inhibitors can prevent the activation of mTOR, which is often observed under diseased conditions [71]. It was shown that the high-fat diet group exhibited elevated mRNA expression levels of mTOR and S6K1 [72]. Conversely, aerobic exercise reduced the expression levels of both genes and enhanced the protein levels of PI3K and AMPK. Nevertheless, It was highlighted that aerobic and resistance exercise can enhance the phosphorylation level of mTOR in normal rats, with resistance training resulting in a higher phosphorylation level than aerobic exercise [73]. Simultaneously, previous research has demonstrated that post-exercise, the phosphorylation level of mTOR in healthy individuals’ exercised and non-exercised legs increased by 45% to 65%. In contrast, there was a 40% increase in AMPK phosphorylation [71]. Therefore, during disease states, physical activity can enhance AMPK function and inhibit mTOR function, leading to anti-inflammatory, anti-proliferative, and autophagy-promoting responses in the body. In good health, exercise increases the level of mTOR phosphorylation, which may serve as an indicator of metabolic demand. In summary, exercise can improve peripheral insulin resistance and maintain stable blood sugar levels, thus delaying the onset of DKD by regulating the skeletal muscle’s glucose uptake through the I RS 1 / GLUT4, AMPK, CaMKII, and mTOR pathways. These pathways are interconnected and exert reciprocal influences on each other.

Exercise Alleviates Renal Stress and Inflammation

Mitochondria regulate the proliferation, differentiation, and inflammation of other cells and produce energy and ROS, as well as mitochondrial self-proliferation and mitochondrial development [74]. As DM mice were given high glucose, their glomerular endothelium cells’ respiratory reserve capacity was significantly decreased. Additionally, the kidneys of the mice showed an increase in ROS and poor renal podocyte mitotic activity compared to normal mice [75]. Meanwhile, a decrease in the mRNA level of silencing information regulator 1 (Sirt1) in renal podocytes treated with high glucose was observed [76]. Additionally, they found that progranulin, a precursor of renal granuloprotein in DM mice, was enhanced. Knocking down the PGRN gene resulted in a significant decrease in the expression level of the Sirt1 gene and a considerable increase in the acetylation level of PGC-1α. Extra proteinuria and an amplified renal inflammatory response can result from DKD-related protein misfolding in the endoplasmic reticulum, impacting protein expression and glycosylation. Furthermore, the endoplasmic reticulum can generate a specific quantity of ROS through the process of nitric oxide synthase (NOS) decoupling reaction [77].

The initial sign of DKD is glomerular endothelial cell (GEC) malfunction. Subsequently, the kidneys may become dysfunctional due to prolonged hyperglycemia and elevated ROS. Both NO levels and the expression of the visceral NOS gene were suppressed [78,79]. Furthermore, AGEs persist in the kidney, where they bind to collagen covalently and continue to accumulate. This process not only causes an increase in the thickness of the glomerular basement membrane and stimulates mesangial cells to produce more extracellular matrix (ECM) but also triggers the activation of nuclear factor kappa-B (NF-κB) and PI3K/AKT/mTOR pathways, leading to a decrease in the levels of antioxidant enzymes, glutathione, and NOS [80,81]. Also, the polyol route can increase fructose and decrease coenzyme I (NADH), and an increase in NADH can increase ROS production through the mitochondrial electron respiratory chain, among other things. Additional glycerin can be generated by glycolysis and the tricarboxylic acid cycle [82]. Prolonged elevation of blood sugar levels and diglycerol can also trigger the activation of the protein kinase C (PKC) pathway. This pathway not only suppresses the expression of the NOS gene but also activates the NF-κB pathway [83]. In the meantime, It was shown that the renal tubulointerstitial of DM mice had transformed growth factor-β1 in addition to an increase in PKC mRNA [84]. The mRNA levels of collagen, fibronectin I, fibronectin III, and fibronectin IV were upregulated by TGF-β1. Overall, oxidative stress and inflammation in the kidneys affected by DKD are attributed to various contributing variables. The main contributors to renal oxidative stress and inflammation include renal mitochondrial dysfunction, renal endothelial cell dysfunction, AGE aggregation, the polyol pathway activation, and the PKC pathway. When these factors interact, they can also result in the loss of kidney-related structural function and apoptosis of related cells. In light of this, DKD’s trajectory will inevitably deteriorate.

The lack of sufficient data from intervention trials on the effects of exercise in patients with diabetes is a significant challenge in DKD research. This gap underscores the pressing need to thoroughly investigate the intricacies of designing and conducting exercise-based intervention studies in this particular group. It is crucial to address these difficulties and develop strategies to overcome them to advance our understanding and establish evidence-based exercise guidelines for managing DKD. Acquiring a sufficient number of participants who fulfill the specific criteria for DKD can be challenging. Additionally, maintaining their ongoing involvement throughout the study was difficult, mainly because of the extensive time commitment and possible fluctuations in participants’ health. The heterogeneity in disease progression, coexisting medical conditions, and individual patient reactions to exercise challenges in establishing standardized intervention protocols. The presence of heterogeneity in a study can diminish the clarity of the outcomes, thereby impeding the ability to derive generalized conclusions. Ensuring compliance with prescribed exercise protocols is a significant obstacle. Physical restrictions, lack of motivation, or absence of immediate benefits may impact participant compliance [85]. Close monitoring is necessary for individuals with different stages of DKD and comorbidities because of the potential risk of adverse events associated with exercise [86]. However, this monitoring method requires a significant amount of resources. Measuring the impact of exercise on DKD progression with precision requires intricate and frequently invasive procedures, which may sometimes only be practical or morally justified.

Recruitment can be improved through the use of social media, patient registries, and community engagement. Offering incentives, ongoing support, and regular feedback can enhance retention. Tailored exercise plans that consider an individual’s comorbidity profile, disease stage, and personal preferences can improve adherence and reduce safety risks. The use of telehealth and digital monitoring tools can provide immediate supervision, increase participant involvement, and ensure compliance with exercise protocols [87,88]. By involving a team of healthcare professionals, including nephrologists, endocrinologists, exercise medical specialists, and physical therapists, a comprehensive strategy can be developed to effectively manage participants’ health, resulting in improved safety and effectiveness of therapy. A combination of subjective and objective evaluations, such as biomarkers, physical fitness assessments, and patient-reported outcome measures, can be used to assess progress. Extensive calculations are crucial for researchers to devise and execute exercise intervention trials for patients with diabetes, particularly those with DKD. Such endeavors are instrumental in filling the existing gaps in knowledge and devising future clinical protocols, thereby enhancing the quality of care and outcomes for patients with DKD.

Exercise Eases Oxidative Stress in Kidneys

DM-obese rats that participated in 8 weeks of aerobic exercise saw increased NO and eNOS in their kidneys and decreased lipid peroxidation in the renal cortex [89,90]. Levels of endothelial nitric oxide synthase (iNOS) decreased. This intervention effectively reduced the renal sinus fat area of overweight or obese individuals, with the most notable impact observed after six months [91]. Furthermore, It was demonstrated that moderateintensity aerobic exercise might lower the amount of TGF-β1 mRNA expression in the renal interstitium, the amount of NF-κB gene expression, and the number of macrophages and lymphocytes in the glomerulus of DM mice [92]. Furthermore, researchers noted that aerobic exercise can increase the expression of the SIRT1 gene in the kidneys of mice with DM while inhibiting the acetylation of NF-κB [93]. In the study conducted, it was found that aerobic exercise reduced the level of ROS in the kidneys and enhanced the overall activity of superoxide dismutase in mice with DKD [94]. The protein level of nuclear factor erythroidrelated factor 2 (Nrf2) and heme oxygenase-1 in proximal tubules can also be increased through the Nrf2/HO-1 pathway. Higher protein concentration was observed in HO-1. Furthermore, in a clinical setting, it was implemented a regimen of lower limb power cycling three times per week for 4 weeks to engage dialysis patients in physical exercise [95]. The objective was to decrease the concentration of malondialdehyde (MDA) in the bloodstream. Remarkably, the MDA levels significantly reduced after 16 weeks of continuous exercise. On the other hand, while the mRNA expression levels of Nrf2 mRNA and glutathione peroxidase (GSHPx) increased after the three months of anti-resistance exercise administered to patients with CKD, the expression levels of NF-κB did not shift significantly [96]. Simultaneously, It was noted that the levels of uric acid, ROS, and inducible nitric oxide synthase (iNOS) protein in healthy rats were markedly elevated compared to the control group following intense anti-resistance exercise [97]. These changes were accompanied by increased glomerular volume, the basement membrane’s thickening, and the mesangial matrix’s proliferation. In summary, the activation of the Nrf2/ NF-κB, SIRT1/NF-κB, and Nrf2/HO-1 pathways, as well as the upregulation of antioxidant enzyme activity and an increase in NO production, are the mechanisms by which exercise intervenes on renal oxidative stress and inflammation in DKD. Further research is necessary to determine whether resistance exercise is appropriate for clinical joint intervention and how to arrange the amount of exercise, even though it can raise the expression levels of Nrf2 and GPS-Px. It is also unclear how precisely resistance exercise affects DKD.

Exercise Influence on the Renin-Angiotensin- Aldosterone Pathway

The RAAS is extensively present throughout the human body and is crucial in maintaining the balance of blood flow dynamics. This is achieved by carefully controlling the equilibrium of water, electrolytes, and circulating blood pressure. The RAAS consists of two axes: vasoconstrictor and vasodilator. Within the ascending axis, renin catalyzes the conversion of angiotensinogen into angiotensin I (AngI), which is subsequently transformed into AngII by angiotensin-converting enzyme (ACE). Angiotensin II (AngII) is the primary regulator of the up-pressure axis by interacting with Angtype II receptor 1 (AT1R). This interaction causes constriction of tiny arterioles throughout the body, stimulates the kidneys to reabsorb water and sodium, and releases aldosterone. The depressor axis consists of ACE2, endogenous heptapeptide, AT2R, and Mas receptors [98,99]. In DKD, the ascending axis of the RAAS is constantly stimulated, leading to elevated pressure in the glomerular vein and glomerulus. This, in turn, increases the production of AngII and ROS, resulting in an increase in ECM and the production of transforming growth factor beta-1 (TGF-β1) by mesangial cells. Ultimately, this leads to glomerular sclerosis and fibrosis [100]. The study found that ACE2-transfected DM rats exhibited lower blood pressure, renal sclerosis index, and urine protein excretion [101].

Additionally, endothelial development was linked to TGF-β1 and vascular endothelial growth factor. In superoxide dismutase activity, Ang-(1-7) concentration and the content of Nephrin, a protein associated with podocytes. Thus, in the case of DKD, the ascending axis of the RAAS is excessively stimulated, leading to elevated levels of renal AngII and its associated downstream components. Conversely, the descending axis, renal ACE2, and its associated downstream components are suppressed. The RAAS can increase blood pressure through direct effects on the smooth muscle of tiny arteries and indirectly by promoting the synthesis of aldosterone. Simultaneously, AngII can stimulate aldosterone production by acting on the circular layers of the adrenal cortex [102]. Furthermore, it was observed that the mRNA expression level of renal aldosterone synthetase in DM rats was 12 times higher than in control rats [103]. Furthermore, they found that administering an AT1R antagonist reduced the mRNA expression level of renal aldosterone synthetase. Furthermore, It was highlighted in a separate study that while the blood glucose and kidney aldosterone levels in rats with double adrenal resection and DM were elevated, the plasma aldosterone levels were reduced [104]. Furthermore, following the administration of aldosterone synthetase inhibitors, the blood glucose levels of diabetic rats remained unaltered. The levels of renal aldosterone, NF-κB, and TGF-β1 protein were reduced. Thus, in the context of DKD, the systemic aldosterone system can contribute to the control of the local aldosterone system, and the elevation of local aldosterone levels in the kidney can intensify the kidney’s inflammatory response and further accelerate the progression of DKD.

Motion’s Impact on Renin-Angiotensin-Aldosterone

Research indicates that physical activity can activate the ACE2/Ang-(1-7)/Mas axis and inhibit the ACE/AngII/AT1R axis [105]. Healthy participants could also raise the amount of Ang-(1– 7) in their urine after exercise and maintain their AngII content at a low level [106]. It was found that both aerobic exercise and a combination of aerobic exercise and metformin intervention can decrease the expression level of urine ACE2 in DM mice [107]. This reduction was observed as early as the 2nd week and continued until the 10th week. Furthermore, DM mice’s glomeruli showed higher levels of ACE2 expression following exercise compared to the control group. In the meantime, DM patients with low daily living activities saw increases in their glomerular filtration rate, blood creatinine level, and glycosylated haemoglobin level in the 4-year follow-up survey [108]. Conversely, moderately intense daily living activities could lower the above metabolic level, lessening the adverse effects on the kidneys. Furthermore, It was observed that the serum aldosterone level in obese rats was notably elevated compared to the control group [109]. However, following exercise intervention, the serum aldosterone level in obese rats was significantly reduced. In contrast, It was found that performing 95% OIC exercise led to a substantial increase in serum aldosterone and AngII concentrations in healthy individuals [110]. However, no significant difference was observed between the two groups in the subgroup with less than 75% participation. The OIC exercise exhibits a rising tendency compared to the silent group. However, it is not statistically significant. Furthermore, It was shown that ascending stairs in the early stages of DKD patients results in elevated levels of urine microalbumin and urinary transferrin immunoglobulin excretion [111,112].

In the context of DKD, physical activity can stimulate the ACE2/ Ang-(1-7)/Mas pathway in the RAAS system, leading to a decrease in pressure within the glomerular vein and glomerulus. This, in turn, reduces the production of AngII, ROS, ECM, and TGF-β1, reducing kidney inflammation and the extent of glomerular sclerosis and fibrosis. After exercise, the ascending pressure axiscontrolled aldosterone production also decreased simultaneously. In healthy individuals, the rise in serum aldosterone levels following exercise promotes the reabsorption of sodium ions in bodily fluids and helps maintain a balanced circulating blood volume. Furthermore, engaging in high-intensity exercise might lead to an imbalance in the RAAS.

The Impact of Culture on Physical Rehabilitation

Cultural values and traditions surrounding health, illness, and physical activity can have a significant impact on an individual’s readiness to participate in rehabilitation programs that involve exercise [113,114]. In some cultures, a more rest-oriented approach may be favored when someone is unwell, while in others, a greater emphasis may be placed on natural or holistic remedies rather than structured exercise routines. The influence of family and community, which varies greatly across cultures, can also affect an individual’s participation in rehabilitation programs. Family involvement is crucial in certain cultures for adhering to treatment plans and making healthcare decisions. Disparities in health literacy and communication styles across cultures can also impact how individuals from different backgrounds understand and interact with healthcare providers regarding the use of exercise as a therapeutic intervention. Culturally sensitive communication can help healthcare providers engage with patients and enhance patient education. The effectiveness of physical rehabilitation programs and the use of fitness centers are heavily influenced by an individual’s socioeconomic status [115]. Those with lower status may require assistance in the form of facilities, recreational parks, or safe pedestrian zones. The costs associated with these activities, such as transportation, program fees, and lost wages, can be prohibitively high for individuals with restricted financial resources. In areas with limited resources, healthcare priorities often focus on acute care and infectious diseases, whereas chronic disease management, including physical rehabilitation for DKD, may receive less attention [116].

Discrepancies in accessibility, adherence, and efficacy of physical rehabilitation programs for DKD may stem from the interplay of cultural and socioeconomic factors. Individuals from culturally diverse backgrounds or lower socioeconomic statuses may encounter hindrances when attempting to access healthcare services, which can result in diminished participation in rehabilitation programs and, consequently, suboptimal health outcomes. Thus, to enhance patient participation and adherence, it is crucial to develop exercise and rehabilitation plans that are culturally sensitive and respectful of patient customs and values [117]. Furthermore, utilizing community resources to provide accessible and affordable rehabilitation services can help alleviate socioeconomic barriers. Advocating policies that increase the availability of rehabilitation services for marginalized and economically disadvantaged populations is essential. Conducting research aimed at understanding and addressing cultural and socioeconomic obstacles to effectively managing DKD can provide invaluable insights and inform the development of more targeted interventions. A comprehensive examination of these variables would emphasize the importance of holistic and inclusively managing DKD, leading to more equitable healthcare outcomes for diverse populations.

Conclusions and Future Prospective

In summary, the existing evidence suggests that physical activity may have a positive impact on risk factors associated with disease progression; however, the precise impact on renal function is still under debate [118]. The conclusions reported in recent meta-analyses are influenced by variations in the methodologies and studies included. This ambiguity is further compounded by the diverse methodologies employed in different studies, particularly with regard to the duration and intensity of the exercise programs. Additionally, the commitment of participants to the exercise program is another factor that complicates the establishment of a definitive result.DKD is a form of CKD caused by DM [119,120]. The primary mechanism underlying its development involves the disruption of renal metabolism and hemodynamics due to prolonged exposure to high glucose levels. Exercise delays the progression of DKD by improving glucose regulation, reducing oxidative stress and inflammation in the kidneys, and controlling the RAAS. However, further research is needed to fully understand the precise mechanisms and pathways through which exercise exerts these effects. It is important to note that DKD follows a well-defined trajectory and stage during clinical diagnosis. Patients with CKD often face several barriers that hinder their ability to exercise, which can lead to nonadherence to their treatment plans [121,122]. This complexity highlights the real-world impact of exercise training and complicates the evaluation of the effectiveness of recommended programs. It is crucial to concentrate on making exercise training programs more accessible and motivating to increase compliance, ideally without decreasing the physiological load. Using this approach, researchers can be confident that their investigations will continue to address this core scientific subject. Additional research is necessary, as our understanding of the systems that regulate the influence of exercise on renal function still needs to be improved. Future studies examining the impact of exercise on the progression of DKD should focus on selecting patients with the highest likelihood of benefiting from the intervention. Thus, to accomplish this, it is essential to have a better understanding of the processes by which the kidneys adapt to exercise in order to (1) identify individuals who are at risk of developing the disease and (2) target populations where exercise-induced adaptations are likely to have the most significant effect.

According to current guidelines, patients with non-disease (ND-CKD) ought to engage in moderate aerobic exercise for 150 minutes per week, with strength and flexibility training added at least two days a week [107]. Research in this area should encompass both aerobic and resistance exercises, as they are frequently included in studies that assess their effects on DKD risk variables. Resistance training is particularly important as it encompasses processes that affect inflammatory levels, some of which depend on muscle stretching or have been observed in resistance-only programs. Furthermore, it is unreasonable to exclude either aerobic or resistance exercise, as both have demonstrated advantages for DKD unrelated to kidney function. While the effects of exercise on the course of CKD remain uncertain, there is no evidence of a negative impact from randomized controlled trials (RCTs) thus far. However, it would be premature to include exercise training in licensing or national guidelines based solely on this lack of evidence. Although there is no evidence that exercise interventions harm kidney function, there are several other benefits of increased physical activity. Therefore, doctors should recommend and prescribe exercise more frequently. However, existing studies on the correlation between exercise interventions and DKD require further investigation. Moreover, given the significant risk that DKD poses for cardiovascular disease, it is crucial to conduct exercise load testing before engaging in physical activity to determine the appropriate exercise intensity for a patient’s condition. Future studies, such as cost-effectiveness assessments, may provide sufficient data to support the integration of exercise training with standard care.

Acknowledgment

We express our sincere gratitude to all the participants who generously volunteered their time and effort to take part in this study. Their valuable contributions have significantly advanced our understanding of this field. Additionally, we extend our appreciation to the Natural Science Foundation of Shanxi Province..

Author Contributions

Imran Ali and Shoaib Muhammad designed the review. Syed Shah Zaman Haider Naqvi and Ahmad Mahmood created figures. Lingxi Wei and Wenqi Yan collected data from the literature. Pengyu Yan and Huifang Wang provided guidelines. Huan Li, Muhammad Faiz Khan, and Arshad Mehmood drafted, proofread, and revised the manuscript. Wahid Shah and Hong Liu supervised the review. All authors have read and agreed to the published version of the manuscript.

Funding

This project was funded by the General Project of the Natural Science Foundation of Shanxi Province (201901D111350).

Data Availability Statement

Data available on request from the authors.

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