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Updated: Feb 20, 2026
A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis
Published on: October 26, 2020
Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension
Sonu Kashyap1, Gina Warner2, Zeng Hu1
1Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
Insights
Smad3 deficiency protects kidneys in renovascular hypertension models but causes strain-specific cardiovascular issues. 129 mice showed myocyte necrosis, while C57BL/6J mice experienced aortic dissections, highlighting Smad3
Area of Science:
- Cardiovascular Biology
- Renal Physiology
- Molecular Medicine
Background:
- Renovascular hypertension (RVH) negatively impacts kidney and heart health.
- Transforming growth factor-beta (TGF-β) signaling via Smad3 is implicated in chronic tissue fibrosis.
- Smad3 deficiency protects stenotic kidneys in the 2-kidney 1-clip (2K1C) RVH model but increases sudden cardiac death risk.
Purpose of the Study:
- To investigate the cardiovascular phenotype of Smad3-deficient mice in the 2K1C model of RVH.
- To characterize the strain-specific effects of Smad3 deficiency on cardiovascular complications following renal artery stenosis.
Main Methods:
- Induction of renal artery stenosis (RAS) in Wild-type (WT) and Smad3 knockout (KO) mice (129 and C57BL/6J backgrounds) using a polytetrafluoroethylene cuff.
- Mortality assessment and necropsy following surgical intervention.
- Histological analysis of myocardial tissue at various time points post-surgery to evaluate myocyte necrosis, inflammation, and fibrosis.
- Genetic backcrossing of Smad3 KO mice to the C57BL/6J strain.
Main Results:
- Smad3 KO mice on the 129 background exhibited significantly higher mortality (25.5%) due to myocyte necrosis and associated inflammation (Ccl2, macrophage influx, MMP-9 activity) within 3 days of RAS.
- Both WT and Smad3 KO mice (129 background) developed myocardial fibrosis at later time points; no aortic aneurysms or dissections were noted.
- Smad3 KO mice on the C57BL/6J background showed a high incidence of sudden death (62.5%) at 10-14 days post-RAS, confirmed as aortic dissections.
- The stenotic kidney in Smad3 KO mice remained protected from chronic damage in both genetic backgrounds.
Conclusions:
- Cardiovascular manifestations of Smad3 deficiency in RVH are strain-dependent.
- Myocyte necrosis is a key feature in 129 Smad3 KO mice, whereas aortic rupture occurs in C57BL/6J Smad3 KO mice.
- Further research is needed to elucidate the mechanisms behind these strain-specific cardiovascular responses to Smad3 deficiency and RAS.
Abstract:
Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kidney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10-14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.
