Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease
2017
Pathways implicated in diabetic kidney disease (DKD) are largely derived from animal models. To examine if renin-angiotensin system (RAS) changes in humans are concordant with rodent models, we measured concentration of angiotensinogen (AOG), cathepsin D(CTSD), angiotensin converting enzyme(ACE), ACE2 and enzymatic activities of ACE, ACE2 and aminopeptidase-A in FVB mice 13-20 weeks after streptozotocin (n=9) or vehicle (n=15) and people with longstanding type 1 diabetes, with (n=37) or without (n=81) DKD. In streptozotocin-treated mice, urine AOG and CTSD were 10.4-and 3.0-fold higher than controls, respectively (p-values <0.001). Enzymatic activities of ACE, ACE2 and APA were 6.2-, 3.2- and 18.8-fold higher, respectively, in diabetic animals (p-values <0.001). AngiotensinII was 2.4-fold higher in diabetic animals (p-value 0.017). Compared to people without DKD, those with DKD had higher urine AOG (170 vs. 15μg/g) and CTSD (147 vs. 31μg/g). In people with DKD, urine ACE concentration was 1.8-fold higher (1.4vs. 0.8μg/g without DKD), while its enzymatic activity was 0.6-fold lower (1.0 vs. 1.6 x 10 RFU/g without DKD). Lower ACE activity, not ACE protein concentration, was associated with ACE inhibitor (ACEI) treatment. After adjustment for clinical covariates, AOG, CTSD, ACE concentration and activity remained associated with DKD. In conclusion, in mice with streptozotocin-induced diabetes and humans with DKD, urine concentrations and enzymatic activities of several RAS components are concordantly increased, consistent with enhanced RAS activity and greater angiotensinII formation. ACEI use was associated with a specific reduction in urine ACE activity, not ACE protein concentration, suggesting it may be a marker of exposure to this therapy.
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