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J Am Soc Nephrol. 2014 May;25(5):1050-62. doi: 10.1681/ASN.2013020195. Epub 2014 Apr 10.

Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis.

Author information

1
Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
2
Physiologie et Médecine expérimentale du Cœur et des Muscles, Institut National de la Santé et de la Recherche Médicale U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France;
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Transmission Electron Microscopy Platform, Institut National de la Santé et de la Recherche Médicale U1016, Cochin Institut, Paris, France; Centre National de la Recherche Scientifique UMR81044, Paris, France;
4
The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Pushchino State Institute for Natural Sciences, Pushchino, Moscow Region, Russian Federation;
5
University of Texas Southwestern Medical Center, Dallas, Texas; and.
6
The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom;
7
Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Nephrology Service, Georges Pompidou European Hospital, Assistance Publique Hopitaux de Paris, Paris, France pierre-louis.tharaux@inserm.fr.

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-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total β-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 β-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 β-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.

PMID:
24722437
PMCID:
PMC4005294
DOI:
10.1681/ASN.2013020195
[Indexed for MEDLINE]
Free PMC Article

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