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A Review on Diabetic Nephropathy: New
Insight into Established Therapeutic Approach
Jaheda Akter and Sanjida Islam*
Department of Pharmacy, International Islamic University Chittagong, Bangladesh
Submission: November 22, 2020; Published: March 29, 2021
*Corresponding author: Sanjida Islam, Department of Pharmacy, International Islamic University Chittagong, Bangladesh
How to cite this article: Jaheda A, Sanjida I. A Review on Diabetic Nephropathy: New Insight into Established Therapeutic Approach. Nutri Food Sci Int J. 2021.
10(5): 555798. DOI: 10.19080 10.19080/NFSIJ.2021.10.555798.
Background: Diabetic nephropathy (DN) is a principle cause of morbidity and mortality in both type 1 and type 2 diabetes mellitus. DN plays a major role in development of cardiovascular disease, in particular heart failure, the incidence of which is about 15-fold greater in patient with diabetic nephropathy. Approximately 30-35% of patients with type 1 type 2 diabetes develops diabetic nephropathy. DN is represented by microalbuminuria and macroalbuminuria and morphological changes as like glomerular thickening, interstitial fibrosis, formation of nodular glomerulosclerosis and decreased endothelial cell fenestration. Additionally, the association of renin-angiotensin-aldosterone system, wnt signaling pathway and genetic factors are the major pathway in the progression of diabetic nephropathy.
Conclusion: This review is intended to establish a new insight into traditional therapeutic approach for diabetic nephropathy. Along with potential targets, novel approach such as epigenetic drugs and miRNA modulators may compliment the current therapeutic approach to improve renal function.
Diabetic nephropathy is associated with increased albumin excretion, decreased glomerular filtration rate, glomerular lesion and increased arterial blood pressure . DN can be divided into 5 stages of kidney dilapidation, and symptoms appear in stage 4. All patient should be screened for albuminuria at least once per year for kidney complication. The significant signs of step 4 are swelling of ankles, legs and hands because of water retention, hematuria, fatigue and nausea. If this condition remains untreated may lead stage 5, end-stage renal disease (ESRD) . In stage 5, the kidney can no longer function to meet the daily requirement and microalbuminuria (>300mg/24h), progress to extensive proteinuria (>500mg in 24 h). Various factors linked with end-stage renal diseases are hemodynamic changes, inflammation and hyperglycemia . The mechanism involved in the progression of DN is still on the question. Many researchers have determined an interrelationship between the degree of hyperglycemia and progression of DN complications . As because a number of pathways involved in diabetic nephropathy, treatment should be multi-targeted, encouraging a healthy lifestyle and molecular targets associated in progression of DN. Available treatment procures only symptomatic alleviation and incapable of treating the underlying pathophysiology of diabetic nephropathy.
Studies suggested that patient suffering from diabetic nephropathy have increased serum and urine level of tumor necrosis (TNF)-alpha . It had been reported that TNF-alpha, IL-6, IL-1 associated in the progression of DN, found to be involved in the impairment of interglomerular hemodynamic .
The dysfunctional ACE gene produce excess amount of aldosterone which causes fibrosis of blood vessels and aldosterone is also found to be associated with formation of extracellular matrix and fibronectin by mesangial cells by activation of the smad2-dependent TGFB1 pathway .
Oxidant species produced by oxygen metabolism and are required in different biological operation such as cell signalling, degenerative disease, aging etc . Various pathophysiological mechanisms involved in DN pathogenesis in which increased oxidant species have been recognized as the single underlying
strenuous event therefore, elevated oxidant species accommodates
a decisive central and significant role in the pathogenesis of diabetic
nephropathy. In vitro and in vivo experimental models of diabetes
have determined that metabolic (hyperglycemia, dyslipidaemia)
and hemodynamic (systemic and glomerular hypertension)
insults define the two principal drivers of oxidative stress in the
diabetic kidney . Overexpression of glucose transport because
of metabolic- hemodynamic interaction, synergistically fuels an
increase in oxidant species production and development of DN
and other diabetic microvascular diseases. Oxidant species causes
the damage in all the layers of the glomerular filtration barrier,
functional alterations of the interaction between glomerular
endothelial cells with glycocalyx layer and podocyte .
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been
used for reducing hyperglycemia because SGLT2 is responsible
for reabsorbing of the glucose in the glomerular infiltrate.
Empagliflozin, an SGLT2 inhibitor, slower the progression of
kidney diseases . Dipeptidyl peptidase -4(DPP-4) inhibitors
such as linagliptin and saxagliptin (SAVOR-TIMI 53 trial) known
to reduce the amount of albuminuria .
Aspirin as a non-specific and others specific COX-2 inhibitors
improve glomerular lesion, in pre-clinical models of diabetes .
Purine xanthine oxidase (XO) inhibitor reduce inflammation and
oxidative stress in diabetic nephropathy .
It was reported that statins amend renal dysfunction and
reduce renal injury by inhibition of isoprenylation of Ras and Rho
GTPases. Which may lead to decreased monocyte/macrophage
infiltration and activating protein-1 (AP-1) in the glomerulus,
adhesion of molecules, decreased mesangial proliferation and
decreased accumulation of extracellular matrix and fibrosis .
Avosentan, an endothelin-1 receptor A antagonist, found to
reduce albuminuria. A study conducted on randomized controlled
trial on 56 patients treated with oral bosentan for 4 weeks
improves peripheral endothelial function .
Pyridoxamine can remove free radicals and carbonyl product,
and block the synthesis of AGEs. Pyridoxamine phase II trials
showed the normal renal function had lower average serum
creatinine level. Currently PIONEER -CSG -17 trial investigating to
prove such benefit about use of pyridoxamine . It has been
reported that teneligliptin is a DPP-4 inhibitor with antioxidant.
Under hyperglycemia conditions, up regulated micrRNAs
result in pathogenesis of diabetic nephropathy . It was
suggested, miR-192 & miR-200 contribute to stimulate of TGFbeta
1 and fibrosis, which may consequently cause renal damage
. Therefore, miRNA may inhibit diabetic nephropathy by
regulating various biological processes. Application of kidney
protective miRNAs and knockout of inducing miRNA could be
some of the approaches to restoring renal function in diabetic
Recent studies are gathering the evidence about involvement
of autophagy with DN because of its cryoprotective activity in the
kidney . mTOR may suppress autophagy. mTORC1 inhibitors
such as rapamycin or sirolimus have been found to be effective
as renoprotective agents except for the negative effect on renal
function and proteinuria .
Due to the distinct and complicated pathogenic mechanism
associated with DN the failure rate of potential new drugs in
clinical trials above 90% with only a fistful of these therapies
achieving phase III trials. Summarizing the outcome of recently
completed clinical trials in the past 5 years (2013-2018) and
shown in Table 1 .
Diabetic nephropathy remains one of the most prevalent and
life-threatening complications of diabetes. Diabetic nephropathy
cases increasing rapidly around the world. Recently available
therapies provide only symptomatic relief and not capable to
treat underlying pathophysiology of diabetic nephropathy. This
review has discussed the many factors and pathophysiological
mechanisms associated with the progression of diabetic
nephropathy, targets and therapeutic approaches to reduce renal
impairment and improve kidney function. It also provided with
new insights into the treatment of diabetic nephropathy. Novel
biomarkers holding strong potential requires further clinical
studies. The review also focused on the future prospect of drug
for the treatment of diabetic nephropathy and update of recent
clinical trials of targets for the treatment of diabetic nephropathy.
A combination of therapies with epigenetic drugs and miRNAs
modulators may fulfil the current treatment strategy of diabetic