Hyperglycemia and Renin-Dependent Hypertension Synergize to Model Diabetic Nephropathy

Abstract

Rodent models exhibit only the earliest features of human diabetic nephropathy, which limits our ability to investigate new therapies. Hypertension is a prerequisite for advanced diabetic nephropathy in humans, so its rarity in typical rodent models may partly explain their resistance to nephropathy. Here, we used the Cyp1a1mRen2 rat, in which the murine renin-2 gene is incorporated under the Cytochrome P4501a1 promoter. In this transgenic strain, administration of low-dose dietary indole-3-carbinol induces moderate hypertension. In the absence of hypertension, streptozotocininduced diabetes resulted in a 14-fold increase in albuminuria but only mild changes in histology and gene expression despite 28 weeks of marked hyperglycemia. In the presence of induced hypertension, hyperglycemia resulted in a 500-fold increase in albuminuria, marked glomerulosclerosis and tubulointerstitial fibrosis, and induction of many of the same pathways that are upregulated in the tubulointerstitium in human diabetic nephropathy. In conclusion, although induction of diabetes alone in rodents has limited utility to model human diabetic nephropathy, renin-dependent hypertension and hyperglycemia synergize to recapitulate many of the clinical, histological, and gene expression changes observed in humans.

Metabolic Syndrome, ESRD, and Death in CKD

“…Numerous experimental and population-based studies have shown that insulin resistance and hypertension are associated with glomerular injury and glomerulosclerosis (21)(22)(23), and thus, as expected, impaired glucose metabolism and hypertension were associated with an increased risk for ESRD in this analysis. However, the relationship between other components, such as elevated serum triglycerides and ESRD, low HDL cholesterol, and all-cause mortality, is novel.…”

Gq signaling causes glomerular injury by activating TRPC6

“…The renin-angiotensin system has been suggested to be a disease accelerant in rodent models of diabetic kidney disease (39,40). In support of this hypothesis, overexpression of a renin transgene was found to promote the development of advanced diabetic tion and a mutation in nephrin (NPHS1 R831C) that had previously been reported to cause the autosomal recessive disease congenital nephropathy of the Finnish type.…”

“…The rationale for studying Gq activation in this model is based on the observations that: (a) the reninangiotensin system is a disease accelerant in rodent models of diabetic kidney disease (39,40); and (b) the beneficial actions of AT1 receptor blockers in diabetic nephropathy are mediated by blocking the Gq-coupled AT1 receptor (8,9). In this scenario, signaling cascades activated by Gq may provide the second hit +/+ GqQ>L mice compared with that in either WT controls or Trpc6-KO GqQ>L mice.…”

Recent Advances in Animal Models of Diabetic Nephropathy

“…Increased albuminuria, glomerulosclerosis and, importantly, tubulointerstitial fibrosis have been consistently observed with combined diabetes and hypertension compared with diabetes alone [19,20,21,22]. Cognizant of the specific beneficial effects of renin-angiotensin system inhibition in treating nephropathy, researchers have induced hyperglycaemia in the mRen2 rat, in which a copy of murine renin cDNA is integrated into the genome, leading to renin-dependent hypertension [20].…”