TY - JOUR
T1 - Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis
AU - Lenoir, Olivia
AU - Milon, Marine
AU - Virsolvy, Anne
AU - Hénique, Carole
AU - Schmitt, Alain
AU - Massé, Jean Marc
AU - Kotelevtsev, Yuri
AU - Yanagisawa, Masashi
AU - Webb, David J.
AU - Richard, Sylvain
AU - Tharaux, Pierre Louis
N1 - Publisher Copyright:
Copyright © 2014 by the American Society of Nephrology.
PY - 2014/5/1
Y1 - 2014/5/1
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2013020195
DO - 10.1681/ASN.2013020195
M3 - Article
C2 - 24722437
AN - SCOPUS:84906542664
SN - 1046-6673
VL - 25
SP - 1050
EP - 1062
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 5
ER -