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

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47 Scopus citations

Abstract

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
Volume25
Issue number5
DOIs
StatePublished - May 1 2014

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ASJC Scopus subject areas

  • Nephrology

Cite this

Lenoir, O., Milon, M., Virsolvy, A., Hénique, C., Schmitt, A., Massé, J. M., Kotelevtsev, Y., Yanagisawa, M., Webb, D. J., Richard, S., & Tharaux, P. L. (2014). Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis. Journal of the American Society of Nephrology, 25(5), 1050-1062. https://doi.org/10.1681/ASN.2013020195