Cardiovascular manifestations of renovascular hypertension in diabetic mice
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Abstract
Purpose. Type 2 diabetes is the leading cause of end stage renal disease in the United States. Atherosclerotic renal artery stenosis is commonly observed in diabetic patients and impacts the rate of renal and cardiovascular disease progression. We hypothesized that renal artery stenosis contributes to bilateral renal disease in diabetics. In our original study, we found that leptin-deficient diabetic (db/db) mice subjected to RAS developed severe and bilateral renal disease, with the contralateral (uncuffed) kidney showing features reminiscent of progressive diabetic nephropathy. In non-diabetic mice (WT), the cuffed kidney developed progressive atrophy, but the contralateral kidney showed minimal histopathologic alterations. In doing these studies, we observed increased sudden death in db/db mice with RAS, but not in WT mice with RAS. The objective of this study was to characterize the aortic and cardiac phenotype of db/db mice subjected to RAS. Methods. We developed a murine model of renal artery stenosis by placement of a polytetrafluoroethylene cuff on the right renal artery in db/db mice. We studied 109 WT and 95 db/db mice subjected to Renal artery stenosis (RAS) or sham surgery. Results. The mortality rate of db/db RAS mice was about 23.5%, whereas only 1.5% deaths were observed in WT RAS mice. Interestingly, 60% of mortality in the db/db mice occurred in the first two weeks following RAS surgery. Necropsy showed massive intrathoracic hemorrhage associated with aortic dissection. Aortas from db/db RAS mice showed more smooth muscle dropout, medial disruption, and hemorrhage than aortas from WT mice with RAS. Cardiac tissue from db/db RAS mice had more fibrosis than did cardiac tissue from WT RAS mice. Conclusions. Db/db mice subjected to RAS are prone to develop fatal aortic dissection, which is not observed in WT mice with RAS. The db/db RAS model provides the basis for future studies directed towards defining basic mechanisms underlying the interaction of hypertension and diabetes on the development of aortic lesions.
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2015. Cardiovascular manifestations of renovascular hypertension in diabetic mice. PeerJ PrePrints 3:e1323v2 https://doi.org/10.7287/peerj.preprints.1323v2note This preprint is not peer-reviewed. You may wish to reference the subsequent peer-reviewed version of this article.
Author comment
The title has been changed to reflect cardiac as well as vascular manifestations of diabetic renovascular hypertension. The number of mice evaluated at each time period has been added. New data related to alpha smooth muscle actin expression in aortas has been added.
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Competing Interests
The authors declare that they have no competing interests.
Author Contributions
Sonu Kashyap conceived and designed the experiments, performed the experiments, analyzed the data, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Sean Engel performed the experiments, analyzed the data, wrote the paper, prepared figures and/or tables.
Mazen Osman performed the experiments, analyzed the data.
Yousif Al-Saiegh performed the experiments, analyzed the data.
Asarn Wongjarupong performed the experiments, analyzed the data.
Joseph P Grande conceived and designed the experiments, contributed reagents/materials/analysis tools, wrote the paper, reviewed drafts of the paper.
Animal Ethics
The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):
Mayo Clinic IACUC protocol number A62613
Data Deposition
The following information was supplied regarding data availability:
We have uploaded raw data as supplemental files.
Funding
This study was supported by NIH/NIAID R01 AI100911-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.