Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / pathology
  • Down-Regulation / genetics
  • Down-Regulation / physiology
  • Endothelin-1 / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Podocytes / metabolism*
  • Podocytes / pathology*
  • Receptor, Endothelin A / genetics
  • Receptor, Endothelin A / metabolism
  • Receptor, Endothelin B / genetics
  • Receptor, Endothelin B / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • beta Catenin / metabolism


  • Endothelin-1
  • NF-kappa B
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • beta Catenin