Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

• Published in: Autophagy Vol. 11; no. 7; pp. 1130 - 1145
• Main Authors: Lenoir, Olivia, Jasiek, Magali, Hénique, Carole, Guyonnet, Léa, Hartleben, Björn, Bork, Tillmann, Chipont, Anna, Flosseau, Kathleen, Bensaada, Imane, Schmitt, Alain, Massé, Jean-Marc, Souyri, Michèle, Huber, Tobias B, Tharaux, Pierre-Louis
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03.07.2015
• Subjects: Animals; Apoptosis - drug effects; autophagy; Autophagy - drug effects; Autophagy-Related Protein 5; Cells, Cultured; Development Biology; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Diabetic Nephropathies - prevention & control; diabetic nephropathy; endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - pathology; Endothelial Cells - ultrastructure; Gene Deletion; Glomerular Filtration Rate - drug effects; Glucose - pharmacology; Integrases - metabolism; Life Sciences; Mesangial Cells - drug effects; Mesangial Cells - pathology; Mesangial Cells - ultrastructure; Mice, Inbred C57BL; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - metabolism; Phenotype; podocytes; Podocytes - drug effects; Podocytes - pathology; Podocytes - ultrastructure; proteinuria; sclerosis; Translational Research Paper; CASP3, caspase 3, apoptosis-related cysteine peptidase; MTOR, mechanistic target of rapamycin; endothelial cells; autophagy; DM, diabetes mellitus; GEC, glomerular endothelial cells; proteinuria; STZ, streptozotocin; TEM, transmission electron microscopy; Nphs2, nephrosis 2, podocin; sclerosis; SQSTM1, sequestosome 1; Cdh5, cadherin 5; podocytes; MAP1LC3A/B/LC3A/B), microtubule-associated protein 1 light chain 3 α/β; GFB, glomerular filtration barrier; GBM, glomerular basement membrane; ESRD, end-stage renal disease; α, WT1, Wilms tumor 1; TUBA, tubulin; BUN, blood urea nitrogen; DN, diabetic nephropathy; diabetic nephropathy; ESRD; apoptosis-related cysteine peptidase; GFB; B; sequestosome 1; LC3A; DM; diabetes mellitus; DN; mechanistic target of rapamycin; blood urea nitrogen; caspase 3; microtubule-associated protein 1 light chain 3; Cdh5; GBM; MAP1LC3A; CASP3; STZ; Nphs2; BUN; glomerular endothelial cells; transmission electron microscopy; nephrosis 2; glomerular filtration barrier; GEC; podocin; TUBA; tubulin; cadherin 5; end-stage renal disease; MTOR; streptozotocin; WT1; Wilms tumor 1; glomerular basement membrane; SQSTM1; TEM
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2015.1049799

The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of Atg5 specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelial-specific deletion of Atg5 also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN.