Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension

Gina M. Warner, Jingfei Cheng, Bruce E. Knudsen, Catherine E. Gray, Ansgar Deibel, Justin E. Juskewitch, Lilach O Lerman, Stephen C Textor, Karl A Nath, Joseph Peter Grande

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39 Citations (Scopus)

Abstract

Although the two-kidney, oneclip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the wellestablished role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P < not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/ Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume302
Issue number11
DOIs
StatePublished - Jun 1 2012

Fingerprint

Atrophy
Fibrosis
Hypertension
Kidney
Transforming Growth Factors
Renal Artery Obstruction
Renal Artery
Weight Loss
Blood Pressure
Inflammation
Doppler Ultrasonography
Renovascular Hypertension
Renal Circulation
Polytetrafluoroethylene
Renin
Hyperplasia
Pulse
Exons
Genes

Keywords

  • Renal artery stenosis
  • TGF-β signaling

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension. / Warner, Gina M.; Cheng, Jingfei; Knudsen, Bruce E.; Gray, Catherine E.; Deibel, Ansgar; Juskewitch, Justin E.; Lerman, Lilach O; Textor, Stephen C; Nath, Karl A; Grande, Joseph Peter.

In: American Journal of Physiology - Renal Physiology, Vol. 302, No. 11, 01.06.2012.

Research output: Contribution to journalArticle

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AU - Juskewitch, Justin E.

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