Cardiovascular manifestations of renovascular hypertension in diabetic mice

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. 77 Throughout the course of our studies, we found an increased incidence of sudden death in 78 db/db mice subjected to renal artery stenosis (RAS), which was not observed in wild-type mice 79 subjected RAS. Necropsy of mice available for analysis revealed massive hemothorax and/or 80 hemoperitoneum, which was associated with aortic dissection. 81The objective of this study was to characterize the aortic and cardiac phenotype of db/db 82 mice subjected to RAS. We found that cardiac tissue from db/db RAS mice had more fibrosis 83 than did cardiac tissue from WT RAS mice. Aortas from db/db RAS mice had more smooth 84 muscle dropout, medial disruption, and hemorrhage than did aortas from WT mice with RAS. Figure 4A, B, C, D).164 Cardiac fibrosis was increased in both db/db and WT RAS mice compared to their sham (p = 165 <0.0001) ( Figure 4E). There was a significantly higher degree of fibrosis in db/db RAS mice 166 compared to WT RAS mice (p = 0.045) ( Figure 4E).167 No significant increase in ...