Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets.

Carlamaria Zoja,Christodoulos Xinaris,Daniela Macconi

doi:10.3389/fphar.2020.586892

Abstract

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. The standard treatments for diabetic patients are glucose and blood pressure control, lipid lowering, and renin-angiotensin system blockade; however, these therapeutic approaches can provide only partial renoprotection if started late in the course of the disease. One major limitation in developing efficient therapies for DN is the complex pathobiology of the diabetic kidney, which undergoes a set of profound structural, metabolic and functional changes. Despite these difficulties, experimental models of diabetes have revealed promising therapeutic targets by identifying pathways that modulate key functions of podocytes and glomerular endothelial cells. In this review we will describe recent advances in the field, analyze key molecular pathways that contribute to the pathogenesis of the disease, and discuss how they could be modulated to prevent or reverse DN.

Highlights

Diabetes is a global epidemic that is creating an unsustainable strain on healthcare systems due to its rising incidence worldwide and the costs associated with its chronic complications
To uncover the mechanisms underlying the strong antiproteinuric effect of cAng-(1–7), we focused on podocytes and the glomerular endothelium because of their key role in maintaining an intact glomerular filtration barrier in Diabetic nephropathy (DN) (Weil et al, 2012; Siddiqi and Advani, 2013). cAng-(1–7) ameliorated the defective expression in podocytes of nephrin–the slit diaphragm protein that preserves slit pore integrity and renal filtration capacity–and nestin–a protein involved in the organization of the cytoskeleton–and limited podocyte loss, similar to the ACE inhibitor. cAng (1–7) was better at counteracting glomerular capillary rarefaction, a hallmark of advanced DN (Eleftheriadis et al, 2013), than lisinopril
Diabetic mice with a podocytespecific deletion of RBPj, which is essential for canonical Notch signaling, were partially protected against renal damage, exhibiting lower levels of albuminuria and less podocyte dedifferentiation and loss, accompanied by reduced transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) expression compared with wild-type mice with DN (Niranjan et al, 2008)

Summary

Introduction

Diabetes is a global epidemic that is creating an unsustainable strain on healthcare systems due to its rising incidence worldwide and the costs associated with its chronic complications (http://www.idf. org/diabetesatlas). We focus on the angiotensin converting enzyme 2 (ACE2)/ Angiotensin-(1–7)/Mas receptor axis and the protective effects of cyclic Ang-(1–7) on both podocytes and glomerular endothelial cells in experimental type 2 DN.

Results

Conclusion