Abstract
Kinin B1 receptor (B1R) contributes to insulin resistance, an early event in type 2 diabetes, through the upregulation and activation of the inducible form of nitric oxide synthase (iNOS), pro-inflammatory cytokines and the oxidative stress. This study addresses the hypothesis that inhibition of kininase 1 (carboxypeptidase M, CPM), the key enzyme involved in the biosynthesis of B1R agonists, could exert the same beneficial effects to B1R antagonism in insulin resistance. Male Sprague-Dawley rats were made insulin resistant with a drinking solution containing 10% D-glucose for a period of 9 weeks. Control rats received tap water. During the last week, kininase 1 was blocked with Mergetpa (1 mg kg−1 twice daily, s.c.) and the impact was determined on insulin resistance (HOMA index), metabolic hormone levels, oxidative stress and the expression of several markers of inflammation by western blot and qRT-PCR. Glucose-fed rats displayed hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin resistance, hypertension, positive body weight gain, and enhanced expression of B1R, CPM, iNOS, and IL-1β in renal cortex, aorta and liver. Markers of oxidative stress (superoxide anion and nitrotyrosine expression) were also enhanced in aorta and renal cortex. Mergetpa reversed and normalized most of those alterations, but failed to affect leptin levels and hypertension. Pharmacological blockade of kininase 1 (CPM) exerted similar beneficial effects to a 1-week treatment with a B1R antagonist (SSR240612) or an iNOS inhibitor (1,400 W). These data reinforce the detrimental role of B1R in insulin resistance and recommend CPM as a new therapeutic target.
Highlights
Kininase I-type carboxypeptidases are key enzymes involved in the biotransformation of native kinin agonists (bradykinin (BK) and Lys-BK or kallidin) acting at the constitutive B2 receptor (B2R) into B1 receptor agonists by removing the COOH-terminal Arg residue (Zhang et al, 2013a)
We reported that prolonged inhibition of inducible form of nitric oxide synthase (iNOS) with 1,400 W (Haddad and Couture, 2016) blunted the production of peroxynitrite in the model of insulin resistance, suggesting that this oxidative pathway contributes to the upregulation of the biomarkers of inflammation and represents an important mechanism leading to insulin resistance
Blood glucose level was significantly increased by two-fold (P < 0.05) in overnight-fasted glucose-fed rats compared with control rats, yet after 1-week treatment with Mergetpa (1 mg kg−1 twice daily) glycemia was reduced to level that was no longer significantly different from control values
Summary
Kininase I-type carboxypeptidases are key enzymes involved in the biotransformation of native kinin agonists (bradykinin (BK) and Lys-BK or kallidin) acting at the constitutive B2 receptor (B2R) into B1 receptor agonists (des-Arg9-BK and Lys-des-Arg9-BK) by removing the COOH-terminal Arg residue (Zhang et al, 2013a). An important constitutively active membranebound kininase 1 is carboxypeptidase M (CPM, EC 3.4.17.12), an Arg-carboxypeptidase expressed in a wide variety of cell types, including renal, vascular, neural, pulmonary, and immune cells (Deiteren et al, 2009) This enzyme is strategically localized to regulate kinin activity in inflammatory processes as it is upregulated during tissue damage and by pro-inflammatory. Inhibition of iNOS for 1-week with 1,400 W (N- (3-aminomethyl-benzyl acetamidine) (Haddad and Couture, 2016) or B1R with SSR240612 (Dias et al, 2010; Dias and Couture, 2012a,b) reversed insulin resistance and its associated metabolic features (hyperglycemia, hyperinsulinemia) through the inhibition of the oxidative stress and the nuclear factor NF-κB pathway leading thereby to the concomitant suppression of CPM, B1R, iNOS, and IL-1β overexpression. These studies provided evidence that iNOS and B1R are engaged in a reciprocal upregulation that contributes to insulin resistance and peripheral inflammation
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