Bradykinin and high glucose promote renal tubular inflammation.
BACKGROUND
The role of the kallikrein-kinin system in diabetic nephropathy remains controversial.


RESULTS
High-glucose (HG) super-induced interleukin (IL)-6, CCL-2, transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF) and B(2)K receptor (B(2)KR) mRNA in cultured proximal tubular epithelial cells (PTEC), whereas bradykinin (BK) upregulated IL-6, CCL-2 and TGF-beta mRNA. HG activated mitogen-activated protein kinase (MAPK) p42/p44 and protein kinase C (PKC) signals, whereas BK only activated MAPK. Tubular expression of these mediators and tissue kallikrein 1 (KLK1) was confirmed in human diabetic kidney biopsies. Inhibition of MAPK p42/p44 by PD98059 partially reduced HG and BK induction of IL-6, CCL-2 and TGF-beta, whereas inhibition of PKC by staurosporine partially reduced HG- but not BK-induced overexpression of these cytokines and that of VEGF. Staurosporine and PD98059 synergistically reduced the effect of HG on IL-6, CCL-2 and TGF-beta expression. The B(2)KR blocker, icatibant, downregulated BK- and HG-induced MAPK p42/p44 but not HG-induced PKC activation and partially reduced both HG- and BK-induced IL-6, CCL-2 and TGF-beta secretion. HG stimulated expression of KLK1 and low-molecular-weight kininogen (LMWK) and its downstream effects were attenuated by aprotinin (tissue kallikrein inhibitor). The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, attenuated HG-induced PKC but not HG- or BK- induced MAPK p42/44 activation and reduced HG-stimulated VEGF, along with IL-6, CCL-2 and TGF-beta secretion. Rosiglitazone plus icatibant further reduced these effects of HG.


CONCLUSIONS
In conclusion, HG stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through BK via MAPK signalling and partly through PKC independent of BK. The potential therapeutic role of complementary B(2)KR blockade and PPAR-gamma activation deserves clinical investigation.
Tang
Sydney C W
SC
Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Chan
Loretta Y Y
LY
Leung
Joseph C K
JC
Cheng
Amy Shan
AS
Chan
Kwok Wah
KW
Lan
Hui Yao
HY
Lai
Kar Neng
KN
D000328:Adult; D000368:Aged; D001706:Biopsy; D001920:Bradykinin / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005947:Glucose / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D043782:Receptor, Bradykinin B2 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D047495:PPAR gamma; D043782:Receptor, Bradykinin B2; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; D005947:Glucose; D001920:Bradykinin