We investigated the possible presence of bradykinin (BK) B1 receptor on rat mesangial cells (MC) by binding studies and by the effect of the B1 agonist des-Arg9-BK on intracellular calcium concentration ([Ca2+]i) and DNA synthesis in comparison with the effects of BK. Binding studies demonstrated specific, saturable binding for des-Arg9-[3H]BK inhibited by B1 but not by B2 antagonists. Scatchard analysis revealed a single class of B1 binding site with a maximum density of 15 fmol/mg protein and an affinity of 8.7 +/- 2.4 nM. Saturation and competition studies of 125I-[Tyr0]BK demonstrated the presence of two classes of B2 binding sites [dissociation constant (Kd) = 0.1 and 4 nM, respectively]. On fura-2-loaded adherent MC, both des-Arg9-BK and BK induced a biphasic increase (a transient enhancement followed by a sustained phase) in [Ca2+]i, both in primary culture and in cloned MC. Both the transient and sustained phases of [Ca2+]i induced by des-Arg9-BK were dose dependent, whereas BK induced a transient dose-dependent rise in [Ca2+]i, but the sustained phase remained constant. The increases in [Ca2+]i induced by des-Arg9-BK and BK were specifically abolished by B1 and B2 receptor antagonists, respectively, and showed homologous but not heterologous desensitization. Des-Arg9-BK and BK induced a significant proliferation (tested by cell counting and [3H]thymidine incorporation) of quiescent MC. Furthermore, the effects of des-Arg9-BK and BK were additive on Ca2+ mobilization but not on mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of various fibrotic renal diseases both in humans and in animal models. Unilateral ureteral obstruction (UUO) is an animal model of accelerated renal tubulointerstitial fibrosis that is attenuated by ACE inhibition. Although ACE inhibitors increase bradykinin concentrations in addition to their effect on angiotensin II formation, the role of bradykinin in renal fibrosis has not been studied. We show here that genetic ablation (B2(-/-) mice) or pharmacological blockade of the bradykinin B2 receptor increases UUO-induced interstitial fibrosis in mice, whereas transgenic rats expressing increased endogenous bradykinin show reduced UUO-induced interstitial fibrosis. The increased interstitial fibrosis in B2(-/-) mice was accompanied by a decreased activity of plasminogen activators (PAs) and metalloproteinase-2 (MMP-2), enzymes involved in ECM degradation, suggesting that the protective effects of bradykinin involve activation of a B2 receptor/PA/MMP-2 cascade. This ability of bradykinin to increase PA activity was confirmed in primary culture proximal tubular cells. Thus, in both mice and rats, bradykinin B2 receptor activation reduces renal tubulointerstitial fibrosis in vivo, most likely by increasing ECM degradation.
overweight and obesity are worldwide health concerns leading to many physiological disorders. Recent data highlighted their deleterious effects on brain homeostasis and plasticity, but the mechanisms underlying such disruptions are still not well understood. in this study, we developed and characterized a fast and reliable diet-induced overweight (DIO) model in zebrafish, for (1) studying the effects of overfeeding on brain homeostasis and for (2) testing different preventive and/or therapeutic strategies. By overfeeding zebrafish for 4 weeks, we report the disruption of many metabolic parameters reproducing human overweight features including increased body weight, body mass index, fasting blood glucose levels and liver steatosis. Furthermore, DIO fish displayed blood-brain barrier leakage, cerebral oxidative stress, neuroinflammation and decreased neurogenesis. Finally, we investigated the preventive beneficial effects of A. borbonica, an endogenous plant from Reunion island. overnight treatment with A. borbonica aqueous extract during the 4 weeks of overfeeding limited some detrimental central effects of DIO. In conclusion, we established a relevant DIO model in zebrafish demonstrating that overfeeding impairs peripheral and central homeostasis. This work also highlights the preventive protective effects of A. borbonica aqueous extracts in Dio, and opens a way to easily screen drugs aiming at limiting overweight and associated neurological disorders. Obesity and overweight are defined as excessive body weight characterized by body fat accumulation and could be easily estimated by calculating the body mass index (BMI) 1. Both obesity and overweight are among the main health concerns worldwide. Their prevalence is increasing annually in developing and developed countries and has nearly tripled since 1980s according to the World Health Organization (2019). Overweight and obesity are due to an imbalance between energy intake, storage, and expenditure including interactions with hereditary and environmental factors 2-4. They result in numerous metabolic disorders such as dyslipidemia, non-alcoholic fatty liver, hyperglycemia, insulin resistance, and are characterized by chronic inflammation and oxidative stress 5-7. These pathologies lead to many physiological disorders such as cardiovascular complications as well as the development of type 2 diabetes and contribute to increased morbidities 7,8. In addition to impair peripheral metabolism and homeostasis, overweight and obesity could have a negative impact on central nervous system (CNS) homeostasis, leading to cognitive impairments and dementia 9. Such cognitive defects have been reported in many animal models such as in high fat diet (HFD)-treated rodents displaying hippocampal-dependent cognitive impairments 10,11. Among factors contributing to these cognitive dysfunctions, inflammatory and oxidative stress appear as key players leading to blood-brain barrier (BBB) leakage through decreased expression of tight junction proteins in the hippocampus 12. Other studi...
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