Bradykinin and high glucose promote renal tubular inflammation

Tang, Sydney C.W.; Chan, Loretta Y.Y.; Leung, Joseph C.K.; Cheng, Amy; Chan, Kwok Wah; Lan, Hui‐Yao; Lai, Kar Neng

doi:10.1093/ndt/gfp599

Cited by 63 publications

(74 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, participation of the KKS in DN has become increasingly apparent. We recently observed expression of kallikrein in the proximal tubules of human diabetic kidney tissue, 3 whereas Campell et al 8 reported increased plasma levels of tissue kallikrein in type 2 diabetic subjects. However, there are conflicting in vitro and animal data, as to whether KKS overactivation is good (protective) or bad (destructive) in DN.…”

Section: Discussionmentioning

confidence: 83%

“…As we recently demonstrated upregulation of CCL2 and TGF-b in cultured proximal tubular cells to HG, 3 we next performed immunohistochemical staining to localize these two cytokines in mouse kidney sections. Both CCL2 (proinflammatory) and TGF-b (profibrotic) were present in renal proximal tubules of db/db mice ( Figure 6) and the staining intensity after various treatments mirrored those of the western blots as described above.…”

Section: Interstitial Fibrosismentioning

confidence: 99%

“…4 We have previously reported that rosiglitazone (Ros), a specific synthetic ligand of PPAR-g, partially attenuated advanced glycation end-product-induced tubular inflammation through inhibition of the signal transducer and activator of transcription (JAK/STAT) signal. 5 More recently, we demonstrated that Ros attenuated HG-induced protein kinase C, and together with Icat, conferred additive antiinflammatory effects in cultured tubular cells exposed to HG, 3 and restored nephrin depletion in vivo. 6 Taken together, these in vitro findings suggest a potential therapeutic role of antagonizing B2R or stimulating PPAR-g in DN, and that this combination may confer renoprotection.…”

mentioning

confidence: 91%

“…We recently showed that high glucose (HG) induced B2R expression in cultured renal proximal tubular cells, and that BK stimulated the expression of proinflammatory and profibrotic cytokines in these cells via extracellular signal-regulated kinase (ERK)1/2 activation. 3 Application of the B2R blocker, icatibant (Icat) (HOE 140), downregulated BK-and HG-induced phospho-ERK1/2 signals and the downstream secretion of IL-6, CCL-2, and TGF-b in cultured tubular cells. 3 Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor superfamily.…”

mentioning

confidence: 99%

“…3 Application of the B2R blocker, icatibant (Icat) (HOE 140), downregulated BK-and HG-induced phospho-ERK1/2 signals and the downstream secretion of IL-6, CCL-2, and TGF-b in cultured tubular cells. 3 Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor superfamily. 4 We have previously reported that rosiglitazone (Ros), a specific synthetic ligand of PPAR-g, partially attenuated advanced glycation end-product-induced tubular inflammation through inhibition of the signal transducer and activator of transcription (JAK/STAT) signal.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

Tang

Chan

Leung

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Interstitial Fibrosismentioning

confidence: 99%