Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis

Olivia Lenoir, Marine Milon, Anne Virsolvy, Carole Hénique, Alain Schmitt, Jean Marc Massé, Yuri Kotelevtsev, Masashi Yanagisawa, David J. Webb, Sylvain Richard, Pierre Louis Tharaux

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


The endothelin systemhasemerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transientsmediated by endothelin type A receptors (ETARs) and endothelin typeB receptors (ETBRs).We then generatedmice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre3Ednralox/lox×Ednrblox/lox [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total ß-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total b-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and ß-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.

Original languageEnglish (US)
Pages (from-to)1050-1062
Number of pages13
JournalJournal of the American Society of Nephrology
Issue number5
StatePublished - May 1 2014

ASJC Scopus subject areas

  • Nephrology


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