Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury.
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.
Bledsoe
Grant
G
Department of Biology, Charleston Southern University, 9200 University Boulevard, Charleston, South Carolina 29406, USA. gbledsoe@csuniv.edu
Shen
Bo
B
Yao
Yu-Yu
YY
Hagiwara
Makato
M
Mizell
Brandon
B
Teuton
Michael
M
Grass
Daniel
D
Chao
Lee
L
Chao
Julie
J
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004336:Drug Antagonism; D005839:Gentamicins / Q000633:toxicity*; D007279:Injections, Subcutaneous; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D020840:Tissue Kallikreins / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D018932:Chemokine CCL2; D005839:Gentamicins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; C065679:icatibant; D003094:Collagen; D020840:Tissue Kallikreins; D001920:Bradykinin