Additive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice

Abstract

We recently showed that the bradykinin B2 receptor (B2R) blocker icatibant (Icat) and the peroxisome proliferator-activated receptor-γ 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 α-smooth muscle actin immunostaining, and CCL-2, ICAM-1 and TGF-β 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-β (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.