Additive renoprotective effects of B2-kinin receptor blocker and PPAR-gamma agonist in uninephrectomized db/db mice
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摘要We recently showed that the bradykinin B2 receptor (B2R) blocker icatibant (Icat) and the peroxisome proliferator-activated receptor-g agonist rosiglitazone (Ros) exerted anti-inflammatory effects in renal tubular cells exposed to a diabetic milieu. This study aims to explore whether these effects can be translated to an experimental model of type 2 diabetic nephropathy (DN). db/db mice and their nondiabetic db/m littermates underwent sham operation or uninephrectomy (Unx) at 10 weeks and received vehicle (Veh), metformin (Met), Icat, Ros, or Icat plus Ros for 8 weeks before killing. Among the db/db group with Unx, mice that received Icat or Ros had significantly lower serum creatinine and albuminuria, which was further reduced when Icat and Ros were given in combination. These beneficial effects were not observed in the Met group that achieved similar glycemic control as Ros-treated animals. Likewise, the severity of reactive glomerular and proximal tubular hypertrophy, glomerulosclerosis, interstitial injury, cortical F4/80 and alpha-smooth muscle actin immunostaining, and CCL-2, ICAM-1 and TGF-beta overexpression were all attenuated by Icat and Ros, and these effects were enhanced when both agents were combined. Immunohistochemical staining confirmed the proximal tubular expression of CCL-2 (inflammation) and TGF-beta (fibrosis). Treatment with Icat was associated with decreased B2R, but increased, B1R expression, which was exaggerated in Unx animals. At the signaling level, Icat and Ros reduced extracellular signal-regulated kinase 1/2 and STAT1 activation, respectively. Our results suggest a deleterious role of the kallikrein-kinin system in murine-accelerated DN, which can be ameliorated by the B2R blocker Icat and enhanced by the addition of Ros. This calls for further evaluation of this novel therapeutic approach in more animal models of diabetic nephropathy. Laboratory Investigation (2011) 91, 1351-1362; doi: 10.1038/labinvest.2011.81; published online 2 May 2011
著者Tang SCW, Chan LYY, Leung JCK, Cheng AS, Lan HY, Lai KN
期刊名稱Laboratory Investigation
出版年份2011
月份9
日期1
卷號91
期次9
出版社NATURE PUBLISHING GROUP
頁次1351 - 1362
國際標準期刊號0023-6837
語言英式英語
關鍵詞B2-kinin receptor blockade; diabetic nephropathy; inflammation; PPAR-gamma agonist; renal pathology; signaling; uninephrectomy
Web of Science 學科類別Medicine, Research & Experimental; MEDICINE, RESEARCH & EXPERIMENTAL; Pathology; PATHOLOGY; Research & Experimental Medicine

上次更新時間 2021-10-01 於 00:37