How Is Proteinuric Diabetic Nephropathy Caused by Disturbed Proteostasis and Autophagy in Podocytes?

Abstract

Progression of diabetic nephropathy (DN) is commonly defined by an increase in albuminuria from normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria. Although many therapeutic interventions, including reducing hyperglycemia and intraglomerular pressure, have been shown to slow down the progression of DN, many patients still develop end-stage renal disease. A major difficulty in inducing remission in patients with early DN is the identification of biomarkers that could help to identify patients more likely to progress to end-stage renal disease. Traditional risk factors, such as albuminuria, do not effectively predict DN progression, and other predictors of DN have yet to be characterized and validated. The need for discovering sensitive and robust biomarkers to monitor the decline in renal function and to separate progressors from nonprogressors of DN is therefore of paramount importance. Next to mesangial extracellular matrix deposition and a thickening of basement membranes, progressive loss of glomerular pericytes and “podocytes” and microvascular alterations appear to most closely correlate with the functional renal decline in DN (1–3). Autophagy (“self-eating” in Greek) is a highly regulated lysosomal protein degradation pathway that removes protein aggregates and damaged or excess organelles in order to maintain intracellular homeostasis and cell integrity (4–6). This process was first described in 1957 by Sam Clark Jr. (7), but the term “autophagy” was coined in 1963 by Christian de Duve (8). Autophagy process is well conserved in the evolution from yeast to mammals in various cell types in many organs (9,10). The formation of autophagosomes depends on several …