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Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis

Abstract : The endothelin system has emerged 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 transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre3Ednra lox/lox 3Ednrb lox/lox [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total b-catenin and phospho-NF-kB 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-kB 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 endo-thelin receptors and NF-kB and b-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.
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Soumis le : mardi 14 avril 2020 - 16:13:05
Dernière modification le : vendredi 17 avril 2020 - 14:53:19

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Olivia Lenoir, Marine Milon, Anne Virsolvy, Carole Henique, Alain Schmitt, et al.. Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis. Journal of the American Society of Nephrology, American Society of Nephrology, 2014, 25 (5), pp.1050-1062. ⟨10.1681/ASN.2013020195⟩. ⟨hal-02542297⟩

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