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Recent advances in understanding the biochemical and molecular mechanism of diabetic nephropathy

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Highlights

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    Diabetic nephropathy is a serious complication of diabetes mellitus.

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    Hyperglycemia and other related factors are involved in the pathophysiology of diabetic nephropathy.

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    Understanding of the molecular mechanism may lead to effective therapies.

Abstract

Diabetic nephropathy (DN) is a chronic disease characterized by proteinuria, glomerular hypertrophy, decreased glomerular filtration and renal fibrosis with loss of renal function. DN is the leading cause of end-stage renal disease, accounting for millions of deaths worldwide. Hyperglycemia is the driving force for the development of diabetic nephropathy. The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are: hyperglycemia (causing hyperfiltration and renal injury), advanced glycosylation products, activation of cytokines. In this review article, we have discussed a number of diabetes-induced metabolites such as glucose, advanced glycation end products, protein kinase C and oxidative stress and other related factors that are implicated in the pathophysiology of the DN. An understanding of the biochemical and molecular changes especially early in the DN may lead to new and effective therapies towards prevention and amelioration of DN.

Introduction

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and its prevalence has been increasing worldwide. DN is the leading cause of end stage renal diseases worldwide [1]. DN is characterized by morphological and ultrastructural changes in the kidney including expansion of the molecular matrix and loss of the charge barrier on the glomerular basement membrane [2], [3]. DN is a multifactorial progressive disease where the pathogenesis of the disease is extremely complex involving many different cells, molecules, and factors [4]. The term diabetic nephropathy is used to describe the combination of lesions that often occur concurrently in the diabetic kidney. The most common kidney lesions in people with diabetes are those that affect the glomeruli. The pathogenesis of diabetic nephropathy is complex and still not fully elucidated. This review summarizes the recent advances in understanding the biochemical and molecular mechanism of DN.

Section snippets

Hyperglycemia

Hyperglycemia has generally been considered as the key initiator of kidney damage associated with DN by activation and dysregulation of several metabolic pathways. Hyperglycemia leads to an increase in oxidative stress by exacerbating glucose oxidation and mitochondrial generation of reactive oxygen species (ROS) which cause DNA damage and contributes to accelerated apoptosis [5]. Also increased ROS activate poly (ADP ribose) polymerase (PARP) as a reparative enzyme [6]. PARP inhibits

Advanced glycation end products (AGEs)

Increasing evidence demonstrates that AGEs play a pivotal role in the development and progression of diabetic vascular damage [8]. Further, diabetic patients with end-stage renal disease had almost twice as much AGEs in tissue as diabetic patients without renal disease [8]. Both enhanced formation and decreased clearance are responsible for the accumulation of AGEs in patients with diabetic nephropathy [9], [10]. Accumulation of AGEs in the kidney may contribute to the progressive alteration in

Protein kinase C

Among various signaling kinases, PKC seems to be a centerpiece in the pathogenesis of diabetic nephropathy [16]. Under high glucose ambience it is activated by diacylglycerol (DAG) formed during glycolytic intermediary steps and by ROS generated following AGE: RAGE interactions [17], [18]. Such interactions at the cell membrane activate PKC by increasing the activity of phospholipase C with an increase in intracellular Ca2+ and DAG. This cyclic generation of DAG would suggest an intimate ā€œlevel

Oxidative stress

Increasing evidence in both experimental and clinical studies suggests that there is a close link between hyperglycemia, oxidative stress, and diabetic complications [20], [21]. High glucose induces intracellular ROS directly via glucose metabolism and auto-oxidation and indirectly through the formation of AGEs and their receptor binding [22]. ROS mimic the stimulatory effects of high glucose and upregulate TGF-beta1, PAI-1, and ECM proteins by glomerular mesangial cells, thus leading to

Inflammation

Recent evidence shows an increase in macrophage infiltration and overproduction of leukocyte adhesion molecules in kidneys from diabetic humans and in experimental animal models of diabetes [24], [25]. Chronic inflammation plays an important role in the development of diabetes and its late complications [25], [26], [27], [28]. Increasing evidence points to critical roles of pro-inflammatory cytokines in pathogenesis of diabetic nephropathy. For example, interleukin 1 (IL-1) is believed to

Poly(ADP-ribose) polymerase (PARP) activation

PPARĪ³ (peroxisome-proliferator-activated receptor Ī³) modulates numerous effectors of ECM accumulation [33]. TZDs (thiazolidinediones) are synthetic ligands of PPARĪ³, which is involved in many important physiological processes, including adipose differentiation, lipid and glucose metabolism, energy homoeostasis, cell proliferation, inflammation, reproduction and renoprotection [34], [35]. TZD prevented increase of TGF-Ī² and increase of ECM in cultured human mesangial cells [36], and both

Acknowledgments

This study was supported by a Grant from the Education Department of Heilongjiang Province (11551201), Youth Science Foundation of Heilongjiang Province (QC2010080) and National Natural Science Foundation of China (81100574).

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