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

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 urin...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC4590611
ISSN:	1554-8627 1554-8635
DOI:	10.1080/15548627.2015.1049799