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

Sydney C W Tang1, Loretta Y Y Chan, Joseph C K Leung

  • 1Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong. scwtang@hku.hk

Laboratory Investigation; a Journal of Technical Methods and Pathology
|May 4, 2011
PubMed

Insights

The bradykinin B2 receptor blocker icatibant and rosiglitazone reduce inflammation and kidney damage in diabetic nephropathy mice. Combining these drugs offers enhanced benefits, suggesting a new therapeutic strategy.

Area of Science:

  • Nephrology
  • Endocrinology
  • Pharmacology

Background:

  • Diabetic nephropathy (DN) is a major complication of type 2 diabetes, characterized by inflammation and fibrosis.
  • Previous studies indicated anti-inflammatory effects of bradykinin B2 receptor (B2R) blocker icatibant (Icat) and peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Ros) in renal cells.
  • The kallikrein-kinin system's role in DN pathogenesis requires further elucidation.

Purpose of the Study:

  • To investigate the therapeutic potential of icatibant and rosiglitazone, individually and in combination, in an experimental model of type 2 diabetic nephropathy.
  • To assess the impact of these agents on renal function, histological damage, and inflammatory markers in db/db mice.

Main Methods:

  • db/db mice and db/m littermates underwent uninephrectomy (Unx) and received vehicle, metformin (Met), icatibant (Icat), rosiglitazone (Ros), or Icat + Ros for 8 weeks.
  • Evaluated serum creatinine, albuminuria, glomerular and tubular hypertrophy, glomerulosclerosis, interstitial injury, and immunohistochemical staining for inflammatory markers (F4/80, α-SMA, CCL-2, ICAM-1, TGF-β).
  • Analyzed B2R and B1R expression and signaling pathways (ERK1/2, STAT1).

Main Results:

  • Icat and Ros significantly reduced serum creatinine and albuminuria in uninephrectomized db/db mice, with additive benefits when combined.
  • Both agents attenuated renal hypertrophy, glomerulosclerosis, interstitial injury, and inflammatory/fibrotic marker overexpression, effects enhanced by combination therapy.
  • Icat treatment altered B2R and B1R expression, reduced ERK1/2 activation, while Ros reduced STAT1 activation.

Conclusions:

  • The bradykinin B2 receptor pathway plays a detrimental role in accelerated diabetic nephropathy.
  • Icatibant and rosiglitazone demonstrate significant renoprotective effects, with combination therapy offering enhanced benefits.
  • This novel therapeutic approach warrants further investigation in preclinical models of diabetic nephropathy.

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