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 proliferatoractivated 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 a-smooth muscle actin immunostaining, and CCL-2, ICAM-1 and TGF-b 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-b (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.

BMP7 reduces inflammation and oxidative stress in diabetic tubulopathy

“…Unx db/m mice showed a slight increase in systolic blood pressure and serum BUN (P < 0.05) after 8 weeks of treatment; however, Unx did not show any effect on these parameters in db/db mice. As reported in our previous study [31], Unx markedly exaggerated UACR and serum BUN level in db/db mice compared with sham-operated db/db mice in this study. Average UACR of Unx-db/db vehicle group was 2-fold higher than Unx db/db mice receiving BMP7 injection (8612 + − 2037 μg/mg compared with 3549 + − 816.2 μg/mg, P = 0.036).…”

“…At the age of 9 weeks, mice underwent uninephrectomy (Unx) or sham operation as described previously [31]. Briefly, a dorsalventral incision was made on the right side of the abdominal cavity in anaesthetized mice, the right renal pedicle was identified and ligated followed by carefully dissected out of the kidney.…”

Global Renal Gene Expression Profiling Analysis in B2-Kinin Receptor Null Mice: Impact of Diabetes

“…Polymorphisms in the human B 2 R have been linked to increased albuminuria in diabetic patients and to the development of chronic renal failure [28], [29]. In addition, blockade of B 2 R markedly reduced the proteinuria in STZ-diabetic mice and inhibition of B 2 R ameliorated the accelerated nephropathy in uninephrectomized db/db mice, lending support to the pathogenic role of B 2 R in DN [30], [31].…”

Tissue Kallikrein Mediates Pro-Inflammatory Pathways and Activation of Protease-Activated Receptor-4 in Proximal Tubular Epithelial Cells

“…High glucose induced KLK1 and B2R expression in cultured PTEC and in human proximal tubules of the diabetic kidney [9]. Further in vivo data showed that treatment of the diabetic db/db mice with icatibant, a B2R antagonist, partially attenuated proteinuria and histological lesions in renal tissues [16]. In addition, the deletion of B2R protected against the development of streptozotocin (STZ)-induced DN [17].…”