Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease

Jan Wysocki, Anne Goodling, Mar Burgaya, Kathryn Whitlock, John Ruzinski, Daniel Batlle, Maryam Afkarian

    Research output: Contribution to journalArticle

    14 Scopus citations

    Abstract

    The pathways implicated in diabetic kidney disease (DKD) are largely derived from animal models. To examine if alterations in renin-angiotensin system (RAS) in humans are concordant with those in rodent models, we measured concentration of angiotensinogen (AOG), cathepsin D (CTSD), angiotensinconverting enzyme (ACE), and ACE2 and enzymatic activities of ACE, ACE2, and aminopeptidase-A in FVB mice 13-20 wk after treatment with streptozotocin (n = 9) or vehicle (n = 15) and people with long-standing 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 in controls, respectively (P < 0.001). Enzymatic activities of ACE, ACE2, and APA were 6.2-, 3.2-, and 18.8-fold higher, respectively, in diabetic animals (P < 0.001). Angiotensin II was 2.4-fold higher in diabetic animals (P = 0.017). Compared with people without DKD, those with DKD had higher urine AOG (170 vs. 15 μg/g) and CTSD (147 vs. 31 μg/g). In people with DKD, urine ACE concentration was 1.8-fold higher (1.4 vs. 0.8 μg/g in those without DKD), while its enzymatic activity was 0.6-fold lower (1.0 vs. 1.6 × 109 RFU/g in those without DKD). Lower ACE activity, but not ACE protein concentration, was associated with ACE inhibitor (ACEI) treatment. After adjustment for clinical covariates, AOG, CTSD, ACE concentration, and ACE activity remained associated with DKD. In conclusion, in mice with streptozotocin-induced diabetes and in humans with DKD, urine concentrations and enzymatic activities of several RAS components are concordantly increased, consistent with enhanced RAS activity and greater angiotensin II formation. ACEI use was associated with a specific reduction in urine ACE activity, not ACE protein concentration, suggesting that it may be a marker of exposure to this widely-used therapy.

    Original languageEnglish (US)
    Pages (from-to)F487-F494
    JournalAmerican Journal of Physiology - Renal Physiology
    Volume313
    Issue number2
    DOIs
    StatePublished - Aug 2 2017

    Keywords

    • Aminopeptidase-A
    • Angiotensin-converting enzyme
    • Angiotensin-converting enzyme 2
    • Angiotensinogen
    • Cathepsin D
    • Diabetic kidney disease
    • Renin-angiotensin system

    ASJC Scopus subject areas

    • Physiology
    • Urology

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