Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis.
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.
Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
Olivia
O
Lenoir
Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
Marine
M
Milon
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;
Anne
A
Virsolvy
Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
Carole
C
Hénique
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;
Alain
A
Schmitt
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;
Jean-Marc
JM
Massé
The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Pushchino State Institute for Natural Sciences, Pushchino, Moscow Region, Russian Federation;
Yuri
Y
Kotelevtsev
University of Texas Southwestern Medical Center, Dallas, Texas; and.
Masashi
M
Yanagisawa
The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom;
David J
DJ
Webb
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;
Sylvain
S
Richard
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.
Pierre-Louis
PL
Tharaux
D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D019332:Endothelin-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology*; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
D019332:Endothelin-1; D016328:NF-kappa B; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D051176:beta Catenin