title: Signaling Rho-kinase mediates inflammation and apoptosis in T cells and renal tubules in cisplatin nephrotoxicity.
abstract: Nephrotoxicity is a frequent complication of cisplatin-induced chemotherapy, in which T cells are known to promote acute kidney injury (AKI). Apoptosis and necrosis of tubules and inflammatory events also contribute to the nephrotoxicity. A delineation of the mechanisms that underlie the inappropriate renal and tubular inflammation can thus provide important insights into potential therapies for cisplatin-induced AKI. Rho-kinases are known to act as molecular switches controlling several critical cellular functions, including cell migration, cytokine production, and apoptosis. Here, we show that the Rho-kinase inhibitor fasudil attenuated cisplatin nephrotoxicity, resulting in less histological damage, improved renal function, and the infiltration of fewer leukocytes into the kidney. Renal nuclear factor-κB activation and apoptosis were reduced, and the expressions of proinflammatory renal cytokine and chemokine mRNA were decreased. Urinary and renal kidney injury molecule-1 (Kim-1) expression was also reduced, a finding that is consistent with diminished kidney injury. In the current study, we also showed that fasudil could be protective of the impaired tubules. In vitro, fasudil reduced the apoptosis (annexin-V+PI cells) and cytokine production (tumor necrosis factor+ cells) in T cells and the apoptosis (annexin-V+PI cells) and tubular damage (Kim-1+ cells) in proximal tubular cells by flow cytometric analysis. As Rho-kinase plays an important role in promoting cisplatin nephrotoxicity, inhibiting Rho-kinase may be a therapeutic strategy for preventing cisplatin-induced AKI.
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan yuji0516@med.kindai.ac.jp.
authors: Yuji
authors: Y
authors: Nozaki
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Koji
authors: K
authors: Kinoshita
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Shoichi
authors: S
authors: Hino
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Tomohiro
authors: T
authors: Yano
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Kaoru
authors: K
authors: Niki
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Yasuaki
authors: Y
authors: Hirooka
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Kazuya
authors: K
authors: Kishimoto
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Masanori
authors: M
authors: Funauchi
authors: Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan.
authors: Itaru
authors: I
authors: Matsumura
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D002945:Cisplatin; D018920:Coculture Techniques; D019610:Cytoprotection; D004195:Disease Models, Animal; D000072596:Hepatitis A Virus Cellular Receptor 1; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D020556:Neutrophil Infiltration / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D018836:Inflammation Mediators; D008565:Membrane Proteins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; C049347:fasudil; D002945:Cisplatin
keywords: AKI; Rho-kinase; cisplatin