Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease

Brianna Dufek, Daniel T. Meehan, Duane Delimont, Linda Cheung, Michael Anne Gratton, Grady Phillips, Wenping Song, Shiguang Liu, Dominic E Cosgrove

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Recent work demonstrates that Alport glomerular disease is mediated through a biomechanical strain-sensitive activation of mesangial actin dynamics. This occurs through a Rac1/CDC42 cross-talk mechanism that results in the invasion of the subcapillary spaces by mesangial filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane, including laminin 211, which activates focal adhesion kinase in podocytes culminating in the up-regulation of proinflammatory cytokines and metalloproteinases. These events drive the progression of glomerulonephritis. Here we test whether endothelial cell-derived endothelin-1 is up-regulated in Alport glomeruli and further elevated by hypertension. Treatment of cultured mesangial cells with endothelin-1 activates the formation of drebrin-positive actin microspikes. These microspikes do not form when cells are treated with the endothelin A receptor antagonist sitaxentan or under conditions of small, interfering RNA knockdown of endothelin A receptor mRNA. Treatment of Alport mice with sitaxentan results in delayed onset of proteinuria, normalized glomerular basement membrane morphology, inhibition of mesangial filopodial invasion of the glomerular capillaries, normalization of glomerular expression of metalloproteinases and proinflammatory cytokines, increased life span, and prevention of glomerulosclerosis and interstitial fibrosis. Thus endothelin A receptor activation on mesangial cells is a key event in initiation of Alport glomerular disease in this model.

Original languageEnglish (US)
Pages (from-to)300-310
Number of pages11
JournalKidney International
Volume90
Issue number2
DOIs
StatePublished - Aug 1 2016

Fingerprint

Endothelin A Receptors
Glomerular Basement Membrane
Pseudopodia
Mesangial Cells
Metalloproteases
Endothelin-1
Actins
Cytokines
Focal Adhesion Protein-Tyrosine Kinases
Podocytes
Laminin
Glomerulonephritis
Proteinuria
Small Interfering RNA
Cultured Cells
Fibrosis
Up-Regulation
Endothelial Cells
Hypertension
Messenger RNA

Keywords

  • Alport syndrome
  • actin dynamics
  • endothelin
  • glomerulonephritis

ASJC Scopus subject areas

  • Nephrology

Cite this

Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease. / Dufek, Brianna; Meehan, Daniel T.; Delimont, Duane; Cheung, Linda; Gratton, Michael Anne; Phillips, Grady; Song, Wenping; Liu, Shiguang; Cosgrove, Dominic E.

In: Kidney International, Vol. 90, No. 2, 01.08.2016, p. 300-310.

Research output: Contribution to journalArticle

Dufek, B, Meehan, DT, Delimont, D, Cheung, L, Gratton, MA, Phillips, G, Song, W, Liu, S & Cosgrove, DE 2016, 'Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease', Kidney International, vol. 90, no. 2, pp. 300-310. https://doi.org/10.1016/j.kint.2016.02.018
Dufek B, Meehan DT, Delimont D, Cheung L, Gratton MA, Phillips G et al. Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease. Kidney International. 2016 Aug 1;90(2):300-310. https://doi.org/10.1016/j.kint.2016.02.018
Dufek, Brianna ; Meehan, Daniel T. ; Delimont, Duane ; Cheung, Linda ; Gratton, Michael Anne ; Phillips, Grady ; Song, Wenping ; Liu, Shiguang ; Cosgrove, Dominic E. / Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease. In: Kidney International. 2016 ; Vol. 90, No. 2. pp. 300-310.
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