title: Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury.
abstract: 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.
authors.affiliation: Department of Biology, Charleston Southern University, 9200 University Boulevard, Charleston, South Carolina 29406, USA. gbledsoe@csuniv.edu
authors.forename: Grant
authors.initials: G
authors.lastname: Bledsoe
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.forename: Yu-Yu
authors.initials: YY
authors.lastname: Yao
authors.forename: Makato
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Brandon
authors.initials: B
authors.lastname: Mizell
authors.forename: Michael
authors.initials: M
authors.lastname: Teuton
authors.forename: Daniel
authors.initials: D
authors.lastname: Grass
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
mesh_terms: 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
chemical_list: 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