New Insights on Diabetic Nephropathy

Review Article

J Endocr Disord. 2016; 3(1): 1022.

New Insights on Diabetic Nephropathy

Dahan I, Farber E, Jabali H and Nakhoul F*

Nephrology and Hypertension Division, Bar-Ilan University, Israel

*Corresponding author: Nakhoul F, Nephrology and Hypertension Division, Baruch-Padeh Poriya Medical Center Faculty of Medicine in Galilee Bar Ilan University, Ramat Gan, Israel

Received: April 28, 2016; Accepted: July 14, 2016; Published: July 18, 2016


Diabetic Nephropathy (DN) is a long-standing complication of Diabetes Mellitus (DM) and is responsible for more than 40% of end-stage renal disease cases in developed countries. The pathogenesis of DN is multifactorial inclusing genetic and environmental factors. Traditional risk factors and glycemic control are important but inadequate for predicting the incidence and severity of DN. Different pathways are involved in the pathogenesis of DN. Hyperglycemia accelerates oxidative stress with increased production of free radicals.

Reactive oxygen species, particularly those derived from iron, have been implicated in the increase of oxidative stress injury in the Proximal Convolute Tubules and glomeruli with progression of DN. Polymorphic genetic loci encoding variants in enzymes protecting against iron-induced oxidative stress and apoptosis, serve as potential susceptibility determinants for the development of DN. The major function of the Haptoglobin protein is to bind and modulate the fate of extra-corpuscular hemoglobin and its iron cargo. Since Iron plays a major role in the development of DN it may be a therapeutic target for slowing the nephropathy progression.

A combination of glycemic and blood pressure control, utilizing renin angiotensin-aldosterone system RAAS blockers, has been a mainstay of treatment to slow DN progression. Inhibition of RAAS plays a pivotal role in treatment of chronic diabetic kidney diseases. However, reversal of the course of DN or at least long-term stabilization of renal function is often difficult to achieve, and many patients still progress to end-stage renal disease.

In the current review we suggested some integrated mechanisms involved in DN progression.

Keywords: Diabetic nephropathy; Oxidative stress; Klotho; Autophagy; Vitamin- D


ACEI: Angiotensin Converting Enzyme Inhibitor; ATG: Autophagy-Related Genes; CDKD: Chronic Diabetic Kidney Disease; DN: Diabetic Nephropathy; DM: Diabetes Mellitus; VDR: Vitamin D Receptor; ER: Endoplasmic Reticulum; FGFR1: Fibroblastic Growth Factor-Receptor 1; Hp: Haptoglobin; HG: Hyperglycemia; PCT: Proximal Convolute Tubule; RAAS: Renin Angiotensin Aldosterone System; ROS: Reactive Oxygen Species; SNP’s: Small Nucleotide Polymorphism; TGF- β: Transforming Growth Factor β


Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease and dialysis throughout the world. The establishment of novel, effective therapeutic strategies is, therefore required. Proteinuria and/or albuminuria are a sign of glomerular lesions in DN. These lesions can subsequently develop into tubulointerstitial lesions that lead to renal dysfunction. Clinically, therefore, reducing proteinuria is considered a principal therapeutic target to improve renal outcomes in patients with DN. The pathogenesis of DN involves altered intracellular metabolism associated with hyperglycemia, including the activation of protein kinase C, the accumulation of advanced glycation end-products, oxidative stress, altered apoptosis and autophagy [1]. Moreover, hemodynamic changes such as systemic and glomerular hypertension related to hyperactivation of the renin-angiotensin aldosterone system are also involved in DN [2].

Compared with several proteinuric kidney diseases, the renal prognosis of patients with DN is extremely poor. This suggests that the diabetic condition makes various renal cells vulnerable to damage. Cells have evolved several mechanisms to cope with stress and to maintain cellular homeostasis, such as the anti-oxidative stress response and the Endoplasmic Reticulum (ER) stress response [3,4]. In addition, autophagy is an intracellular catabolic processes, in which proteins and organelles are degraded via lysosomes to maintain intracellular homeostasis under certain cytotoxic stress conditions, including hypoxia and ER stress as appears in DN [5]. The recent pathways involved in the generation and progression of DN are the Haptoglobin (Hp) and Klotho proteins, Vitamin D-Vitamin D Receptor and autophagy [6,7].

Haptoglobin and Oxidative Stress

The Haptoglobin (Hp) genotype is a major determinant of progression of nephropathy in individuals with Diabetes Mellitus (DM). We have previously demonstrated an interaction between the Hp genotype and the DM on the accumulation of iron in renal proximal tubule cells [3,4,8]. Transmission electron microscopy demonstrated a marked accumulation of electron-dense deposits in the lysosomes of proximal tubules cells in Hp 2-2 DM mice [3]. These deposits were iron rich, and are associated with lysosomal membrane lipid peroxidation and loss of lysosomal membrane integrity. Cytosolic and mitochondrial Reactive Oxygen Species (ROS) generations were increased notably by Hyperglycemia (HG) treatment. An increase in apoptosis was also observed in cells subjected to HG, which was assessed by the terminal deoxynucleotidyl Transferase- Mediated Digoxigenin Deoxyuridine Nick End-Labeling (TUNEL) procedure. The apoptosis was accompanied with upregulation of Bax and Cytochrome C. Quantitative analyses confirmed that HG induced mitochondrial fragmentation in a time-dependent manner, concurring with increased intracellular ROS production and apoptosis after HG treatment. Autophagy was marginally increased in early treatment with HG [9].

Citation: Dahan I, Farber E, Jabali H and Nakhoul F. New Insights on Diabetic Nephropathy. J Endocr Disord. 2016; 3(1): 1022. ISSN:2376-0133