Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy

Abstract

One of the earliest clinically detectable abnormalities in diabetic nephropathy is microalbuminuria that eventually progresses to proteinuria. The degree of proteinuria correlates with the progression of glomerulosclerosis and tubulointerstitial fibrosis. In the glomerulus, a typical podocytopathy develops that participates in the initiation of glomerulosclerosis and the accelerated plasma protein leakage across the glomerular basement membrane (GBM) into Bowman’s space. Downstream into the tubular compartment, the proteinuria induces proinflammatory and profibrogenetic injury in tubular cells which can facilitate the development of interstitial fibrosis and tubular atrophy. It has long been held that hemodynamic changes and the loss of negatively charged proteoglycans in the GBM are important mediators of proteinuria. More recently, biopsy studies in humans with diabetic kidney disease have provided strong evidence that podocytes are injured very early in the course of nephropathy. This podocytopathy – which is characterized by decreased podocyte number and/or density, GBM thickening and altered matrix composition, and foot process effacement – correlates closely with the development and progression of albuminuria. Components of the diabetic milieu (high glucose, accumulation of glycated proteins, high intrarenal angiotensin II (ANG II), and hypertension-induced mechanical stress) result in activation of cytokine systems, the most important of which are transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor-A (VEGF-A). ANG II-stimulated podocyte-derived VEGF, through a novel autocrine signaling loop, appears to be a major cause of nephrin downregulation and the development of proteinuria. Nephrin is an important protein of the slit diaphragm with anti-apoptotic signaling properties. TGF-β1 causes podocyte apoptosis and an increase in extracellular matrix deposition. As a consequence, the denuded GBM adheres to Bowman’s capsule initiating the development of glomerulosclerosis. Good control of hyperglycemia and hypertension and maximal inhibition of ANG II are essential steps in preventing the development and progression of diabetic nephropathy.

Roles of Angiopoietins in Kidney Development and Disease

“…47 Microalbuminuria in individuals with diabetic nephropathy is considered to arise from increased protein losses in the glomerular filtrate caused by defects in the filtration barrier, which separates the blood circulation from the urinary space. 48 In human and animal diabetic nephropathy, glomerular expression of nephrin is downregulated, 49 and a similar change occurred when Ang-2 overexpression was induced in transgenic (nondiabetic) mice. 43 Experimental models of type 1 diabetes are associated with altered renal expression of angiopoietins.…”

Mechanisms of angiotensin II signaling on cytoskeleton of podocytes

“…Podocyte cell shape changes, such as retraction of FPs and even podocyte loss, occur in minimal-change nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, chronic glomerulonephritis, and diabetic nephropathy. [7][8][9][10][11] Despite decades of research, the physiological and molecular mechanisms of glomerular filtration and its disturbances remain unclear. functionally linked to the actin cytoskeleton ( Fig.…”

Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy

“…Macrovascular complications lead to atherosclerosis and dilated cardiomyopathy [2], while microvascular complications include diabetic nephropathy [3,4] retinopathy [5,6] and neuropathy [7][8][9][10]. The most common of these complications is diabetic neuropathy (DN) occurring in approximately 60% of diabetic patients [11].…”