Regulation of the intrarenal renin‐angiotensin system in diabetic db/db mice

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The rising prevalence of obesity in the US is paralleled by an increase in the prevalence of type II diabetes. Recent studies have highlighted the importance of blockade of the renin-angiotensin system (RAS) in protecting against end-organ kidney damage due to diabetes. The purpose of this study was to examine the intrarenal RAS in diabetic leptin receptor deficient db/db and control mice. In addition, we examined the effect of stimulation of the intrarenal RAS with a low salt (LS) diet in db/db and control mice. Control and db/db male mice fed normal chow were examined at 7 and 14 weeks of age. At 7 weeks, ACE mRNA expression was decreased by 2-fold in the kidney of db/db compared to control. In contrast, ACE2 mRNA expression was increased by 2-fold in kidneys from db/db compared to control. No changes in angiotensinogen or renin gene expression were detected. At 14 weeks, changes in ACE and ACE2 gene expression in the kidney of db/db mice were accompanied by an increase in angiotensinogen and renin mRNA expression. To determine if the kidney RAS responds appropriately to LS challenge in db/db mice, we fed control and db/db mice a LS diet from 7 to 14 weeks of age. Control mice fed a LS diet exhibited a robust increase in renin and ACE mRNA expression in the kidney. In contrast, mRNA expression of RAS components in kidneys from db/db mice fed a LS diet was similar to that of 14 week-old db/db mice fed the chow diet. However, marked kidney hypertrophy was present in db/db mice fed a LS diet. These results demonstrate a shift in the intrarenal RAS of diabetic mice from a renoprotective (7 weeks of age) to a detrimental phenotype (14 weeks of age). In addition, despite the inability to respond to LS challenge to further increase kidney renin expression in db/db mice, renal hypertrophy was apparent, suggesting a deleterious effect of LS diet in diabetic mice.