icatibant and Nephritis--Interstitial

Gentamicin is an aminoglycoside antibiotic that induces severe nephrotoxicity and acute renal failure. In the current project, we investigated the protective effects of tissue kallikrein (TK) protein administration (1 mug/h via osmotic minipumps) on kidney damage, apoptosis, and inflammation both during and after a 10-day regimen of gentamicin (80 mg/kg body weight/day sc) in Sprague-Dawley rats. TK infusion during gentamicin treatment significantly attenuated drug-induced renal dysfunction, cortical damage, and apoptosis. Moreover, TK reduced inflammatory cell accumulation in conjunction with diminished superoxide production and decreased expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. The protective effects of TK were blocked by coinfusion of icatibant (1.3 mug/h), indicating a kinin B2 receptor-mediated signaling event. After cessation of gentamicin treatment, TK infusion for 2 weeks completely restored kidney histology and morphology comparable to that of saline-treated animals. Furthermore, TK reduced gentamicin-induced renal dysfunction and fibrosis as evidenced by decreased myofibroblast and collagen accumulation in the kidney. In vitro, gentamicin increased the number of apoptotic cells and caspase-3 activity, but decreased phosphorylation of the prosurvival kinase Akt, in immortalized rat proximal tubular cells; addition of TK and bradykinin prevented these effects. In conclusion, our findings indicate that kallikrein/kinin prevents and promotes recovery of gentamicin-induced renal injury by inhibiting apoptosis, inflammatory cell recruitment, and fibrotic lesions through suppression of oxidative stress and proinflammatory mediator expression in animals during and after gentamicin treatment.

Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Apoptosis; Blood Pressure; Blood Urea Nitrogen; Bradykinin; Cell Line, Transformed; Chemokine CCL2; Collagen; Disease Models, Animal; Drug Antagonism; Gentamicins; Injections, Subcutaneous; Intercellular Adhesion Molecule-1; Kidney; Male; Nephritis, Interstitial; Rats; Rats, Sprague-Dawley; Recovery of Function; Superoxides; Tissue Kallikreins; Tumor Necrosis Factor-alpha

Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of various fibrotic renal diseases both in humans and in animal models. Unilateral ureteral obstruction (UUO) is an animal model of accelerated renal tubulointerstitial fibrosis that is attenuated by ACE inhibition. Although ACE inhibitors increase bradykinin concentrations in addition to their effect on angiotensin II formation, the role of bradykinin in renal fibrosis has not been studied. We show here that genetic ablation (B2(-/-) mice) or pharmacological blockade of the bradykinin B2 receptor increases UUO-induced interstitial fibrosis in mice, whereas transgenic rats expressing increased endogenous bradykinin show reduced UUO-induced interstitial fibrosis. The increased interstitial fibrosis in B2(-/-) mice was accompanied by a decreased activity of plasminogen activators (PAs) and metalloproteinase-2 (MMP-2), enzymes involved in ECM degradation, suggesting that the protective effects of bradykinin involve activation of a B2 receptor/PA/MMP-2 cascade. This ability of bradykinin to increase PA activity was confirmed in primary culture proximal tubular cells. Thus, in both mice and rats, bradykinin B2 receptor activation reduces renal tubulointerstitial fibrosis in vivo, most likely by increasing ECM degradation.

Topics: Animals; Bradykinin; Cell Division; Collagen; Disease Models, Animal; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fibrosis; Immunoenzyme Techniques; Kidney; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephritis, Interstitial; Plasminogen Activators; Rats; Receptor, Bradykinin B2; Receptors, Bradykinin; Tissue Kallikreins; Ureteral Obstruction