Wang Pamella Huey Mei, Cenedeze Marcos Antonio, Campanholle Gabriela, Malheiros Denise Maria Avancini Costa, Torres Hugo Arruda de Moura, Pesquero João Bosco, Pacheco-Silva Alvaro, Câmara Niels Olsen Saraiva
Laboratório de Imunologia Clínica e Experimental, Division of Nephrology, Universidade Federal de São Paulo, São Paulo, Brazil.
Int Immunopharmacol. 2009 Jun;9(6):653-7. doi: 10.1016/j.intimp.2008.10.018. Epub 2008 Nov 14.
The Kallikrein-kinin system works through activation of two receptors. One constitutive, named B2 receptor (B2R) and another inducible, denominated B1 receptor (B1R). In renal fibrosis, B2R receptor activation appears to be protective, however B1R participation is unveiled. The aim of this study was to analyze how the deletion of the B1R would modify tissue responses after unilateral ureteral obstruction (UUO). For that, B1R knockout (B1KO) and wild-type mice (B1B2WT) were subjected to UUO and sacrificed at days 1, 5 and 14. Renal dysfunction was assayed by urine proteinuria/creatinine ratio and percentage of tubulointerstitial fibrosis. Kidneys were harvested at day 5 to analyze anti and pro-inflammatory molecules expression by real-time PCR. We demonstrated that at all time points, B1KO mice presented lower proteinuria/creatinine ratio from bladder urine. B1KO protection was reinforced by its lower tubular interstitial fibrosis percentage at day 14 (B1B2WT: 12.16+/-1.53% vs. B1KO: 6.73+/-1.07%, p<0.02). UUO was able to induce B1R expression and its highest transcription was achieved at day 5. At this day, B1KO had significant lower expression of pro-inflammatory molecules such as TGF-beta, MCP-1, OPN and IL-6 and higher anti-inflammatory components, as IL-10 and HO-1. Herein, we observed that B1R deletion may be an important component in renal fibrosis prevention.
激肽释放酶-激肽系统通过激活两种受体发挥作用。一种是组成型的，称为B2受体（B2R），另一种是诱导型的，称为B1受体（B1R）。在肾纤维化中，B2R受体激活似乎具有保护作用，然而B1R的参与也被揭示出来。本研究的目的是分析B1R基因缺失如何改变单侧输尿管梗阻（UUO）后的组织反应。为此，将B1R基因敲除（B1KO）小鼠和野生型小鼠（B1B2WT）进行UUO手术，并在第1、5和14天处死。通过尿蛋白/肌酐比值和肾小管间质纤维化百分比来检测肾功能障碍。在第5天采集肾脏，通过实时PCR分析抗炎和促炎分子的表达。我们证明，在所有时间点，B1KO小鼠膀胱尿液中的蛋白尿/肌酐比值较低。B1KO小鼠在第14天较低的肾小管间质纤维化百分比进一步加强了其保护作用（B1B2WT：12.16±1.53% vs. B1KO：6.73±1.07%，p<0.02）。UUO能够诱导B1R表达，其最高转录水平在第5天达到。在这一天，B1KO小鼠促炎分子如转化生长因子-β、单核细胞趋化蛋白-1、骨桥蛋白和白细胞介素-6的表达显著降低，而抗炎成分如白细胞介素-10和血红素加氧酶-1的表达较高。在此，我们观察到B1R基因缺失可能是预防肾纤维化的一个重要因素。
