Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis
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Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. / 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.
In: AUTOPHAGY, Vol. 11, No. 7, 2015, p. 1130-45.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis
AU - Lenoir, Olivia
AU - Jasiek, Magali
AU - Hénique, Carole
AU - Guyonnet, Léa
AU - Hartleben, Björn
AU - Bork, Tillmann
AU - Chipont, Anna
AU - Flosseau, Kathleen
AU - Bensaada, Imane
AU - Schmitt, Alain
AU - Massé, Jean-Marc
AU - Souyri, Michèle
AU - Huber, Tobias B
AU - Tharaux, Pierre-Louis
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Autophagy
KW - Autophagy-Related Protein 5
KW - Cells, Cultured
KW - Diabetic Nephropathies
KW - Endothelial Cells
KW - Gene Deletion
KW - Glomerular Filtration Rate
KW - Glucose
KW - Integrases
KW - Mesangial Cells
KW - Mice, Inbred C57BL
KW - Microtubule-Associated Proteins
KW - Phenotype
KW - Podocytes
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1080/15548627.2015.1049799
DO - 10.1080/15548627.2015.1049799
M3 - SCORING: Journal article
C2 - 26039325
VL - 11
SP - 1130
EP - 1145
JO - AUTOPHAGY
JF - AUTOPHAGY
SN - 1554-8627
IS - 7
ER -
