Signaling Rho-kinase mediates inflammation and apoptosis in T cells and renal tubules in cisplatin nephrotoxicity

被引:28
作者
Nozaki, Yuji [1 ]
Kinoshita, Koji [1 ]
Hino, Shoichi [1 ]
Yano, Tomohiro [1 ]
Niki, Kaoru [1 ]
Hirooka, Yasuaki [1 ]
Kishimoto, Kazuya [1 ]
Funauchi, Masanori [1 ]
Matsumura, Itaru [1 ]
机构
[1] Kindai Univ, Sch Med, Dept Hematol & Rheumatol, Osaka, Osaka 5898511, Japan
关键词
AKI; cisplatin; Rho-kinase; NF-KAPPA-B; INJURY; ACTIVATION; INHIBITOR; FAILURE; FASUDIL; ALPHA; INTERLEUKIN-18; IDENTIFICATION; LYMPHOCYTES;
D O I
10.1152/ajprenal.00362.2014
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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-kappa B 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.
引用
收藏
页码:F899 / F909
页数:11
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