title: Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension.
abstract: Although the two-kidney, one-clip (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 well-established 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.
authors.affiliation: Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Warner
authors.forename: Jingfei
authors.initials: J
authors.lastname: Cheng
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Knudsen
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Gray
authors.forename: Ansgar
authors.initials: A
authors.lastname: Deibel
authors.forename: Justin E
authors.initials: JE
authors.lastname: Juskewitch
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Textor
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
mesh_terms: D000818:Animals; D001284:Atrophy; D003094:Collagen / Q000096:biosynthesis; D003251:Constriction, Pathologic; D005355:Fibrosis; D006978:Hypertension, Renovascular / Q000235:genetics* / Q000473:pathology*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology*; D007677:Kidney Function Tests; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D012078:Renal Artery Obstruction / Q000473:pathology; D012079:Renal Circulation / Q000235:genetics / Q000502:physiology; D012083:Renin / Q000097:blood; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051900:Smad3 Protein / Q000172:deficiency* / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen; D012083:Renin