Proteinuria causes dysfunctional autophagy in the proximal tubule.

Proteinuria causes dysfunctional autophagy in the proximal tubule. Am J Physiol Renal Physiol. 2016 Aug 31;:ajprenal.00125.2016 Authors: Nolin AC, Mulhern RM, Panchenko MV, Pisarek-Horowitz A, Wang Z, Shirihai OS, Borkan SC, Havasi A Abstract Proteinuria is a major risk factor for chronic kidney disease progression. Furthermore, exposure of proximal tubular epithelial cells to excess albumin promotes tubular atrophy and fibrosis, key predictors of progressive organ dysfunction. However, the link between proteinuria and tubular damage is unclear. We propose that pathologic albumin exposure impairs proximal tubular autophagy, an essential process for recycling damaged organelles and toxic intracellular macromolecules. In both mouse primary proximal tubule and immortalized human kidney cells, albumin exposure decreased the number of autophagosomes, visualized by the autophagosome-specific fluorescent markers monodansylcadaverine and GFP-LC3, respectively. Similarly, renal cortical tissue harvested from proteinuric mice contained reduced numbers of autophagosomes on electron micrographs and immunoblot showed reduced steady state LC3-II content. Albumin exposure decreased autophagic flux in vitro in a concentration-dependent manner as assessed by LC3-II accumulation rate in the presence of bafilomycin, an H+-ATPase inhibitor that prevents lysosomal LC3-II degradation. In addition, albumin treatment significantly increased the half-life of...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research