Kinin B1 Receptor Enhances the Oxidative Stress in a Rat Model of Insulin Resistance: Outcome in Hypertension, Allodynia and Metabolic Complications

Abstract

BackgroundKinin B1 receptor (B1R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B1R activation could perpetuate the oxidative stress which leads to diabetic complications.Methods and FindingsYoung Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8–12 weeks. A selective B1R antagonist (SSR240612) was administered acutely (3–30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B1R expression, aortic superoxide anion (O2 •−) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dose-dependently (3–30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O2 •−, NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B1R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O2 •− in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10–100 µM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe8]des-Arg9-BK (20 µM; B1R agonist). Data show that the greater aortic O2 •− production induced by the B1R agonist was blocked only by apocynin.ConclusionsActivation of kinin B1R increased O2 •− through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B1R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B1R gene expression in this model.

Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats

“…the invasive distribution of B1R in the spinal cord of glucose-fed rats [17,23] and in the epileptic and Alzheimer's disease brain [33,37]. This may be explained by its presence on microglia and reactive astrocytes rather than on neuronal elements [33,46,47].…”

“…The brain of 4 rats per group was immediately removed and frozen in 2-methylbutane cooled at −45 to −55 • C with liquid nitrogen and kept at −80 • C. Brains were mounted in a gelatine block, serially cut into 20-m thick coronal sections using a cryostat (between −11 and −13 • C) and stored at −80 • C for 1 month. B1R autoradiography was performed according to previously described procedures [17,23,37]. Tissue sections were thawed at room temperature and incubated for 90 min in a piperazine-N,N -bis[2-ethanesulfonic-acid] (PIPES) buffer (25 mM, pH 7.4) containing 1 mM 1,10-phenanthroline, 1 mM dithiothreitol, 0.014% bacitracin, 0.1 mM captopril, 0.2% protease-free bovine serum albumin (BSA), 7.5 mM magnesium chloride (all reagents from Sigma) and 200 pM [ 125 I]-HPP-desArg 10 -Hoe-140 (specific activity: 1212 Ci/mmol).…”

“…•− ), a marker of oxidative stress in vascular tissues [16][17][18]21,22,28,35]. Most importantly, 1-week treatment with the orally active non-peptide kinin B1R antagonist (SSR240612) or chronic treatment with a diet containing ␣-lipoic acid or N-Acetyl-L-Cysteine, two potent antioxidants, reversed or prevented all these diabetic abnormalities and the induction of B1R in the spinal cord and peripheral tissues [16][17][18]28,35].…”

“…Most importantly, 1-week treatment with the orally active non-peptide kinin B1R antagonist (SSR240612) or chronic treatment with a diet containing ␣-lipoic acid or N-Acetyl-L-Cysteine, two potent antioxidants, reversed or prevented all these diabetic abnormalities and the induction of B1R in the spinal cord and peripheral tissues [16][17][18]28,35]. Hence, the pathologic role for the inducible B1R in diabetes appears linked to the oxidative stress.…”

Signaling Pathways Coupled to Activation of the Kinin B1 Receptor

“…Dias & Couture (2011) used the B1R antagonist, SSR240612 in a rat model of diabetes and insulin resistance, based on the hypothesis that B1R activates signaling pathways that lead to increased oxidative stress and promote insulin resistance (Dias et al, 2010). The use of such an experimental design reversed the effects of glucose on the expression of IL-1 , TNF-, and macrophage CD68 that are linked to the deposition of adipose tissue.…”