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.

Idiopathic Aneurysms of the Ascending Aorta in the Mouse and Rat

“…In contrast, aortic dissection in leptin-deficient (db/db) mice is associated with fatal intrathoracic hemorrhage. 30 One limitation of this report is the retrospective nature of the analysis. Histochemical or immunohistochemical staining could not be performed because the formalin-fixed, paraffin-embedded tissue blocks were archived.…”

“…29 Leptin-deficient (db/db) mice, a model of human type II diabetes with renovascular hypertension, may develop fatal dissection predominantly of the ascending aorta. 30 In large animal species, rupture of the aorta occurs sporadically in horses and cattle. In older breeding stallions, aortic ruptures are most often at the root of the aorta in the right coronary sinus.…”

“…29 Leptin-deficient (db/db) mice, a model of human type II diabetes with renovascular hypertension, may develop fatal dissection predominantly of the ascending aorta. 30…”

“…In contrast, aortic dissection in leptin-deficient (db/db) mice is associated with fatal intrathoracic hemorrhage. 30…”

Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis

“…Long time hyperglycemia was the culprit of organ parafunction ( Drel et al, 2006 ). Their complications include cardiovascular disease, renal disease, retinal disease and neuropathy ( Kashyap et al, 2015 ). The diabetes incidence of our triple transgenic mouse was early-stage and light.…”