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Pharmacological inhibition of Rac1 exerts a protective role in ischemia/reperfusion-induced renal fibrosis

Author:
Liang, Hua, Huang, Jian, Huang, Qiong, Xie, Yong Can, Liu, Hong Zhen, Wang, Han bing
Source:
Biochemical and biophysical research communications 2018 v.503 no.4 pp. 2517-2523
ISSN:
0006-291X
Subject:
bone marrow, botulinum toxin, collagen, extracellular matrix, fibrosis, interleukin-4, kidneys, macrophages, mice, monocytes, pathogenesis, pathophysiology, phenotype, protective effect, risk factors
Abstract:
Acute kidney injury induced by renal ischemia-reperfusion (IR) is a prominent risk factor in the development towards renal fibrosis. Ras-related C3 botulinum toxin substrate 1(Rac1) has been involved in the pathophysiology of fibrotic disorders. But the role of Rac1 in the pathogenesis of IR-induced renal fibrosis is still unknown. Here, we examined the effects of NSC23766, an inhibitor of Rac1, on the progression of renal fibrosis after IR injury. In mice, IR induced Rac1 activation in kidneys. Rac1 inhibition alleviated renal damage and dysfunction. Mice treated with NSC23766 displayed diminished collagen area in the kidneys compared with IR controls, which was associated with reduction of extracellular matrix (ECM) proteins and α-SMA. Furthermore, Rac1 inhibition reduced profibrotic molecules levels in the kidneys of mice with IR. Finally, Rac1 inhibition impaired the accumulation of bone marrow-derived M2 macrophages and the transition of M2 macrophages to myofibroblasts. In cultured mouse monocytes, IL-4 treatment activated Rac1, which was abrogated by NSC23766. Moreover, application with IL-4 induced polarization of monocytes to M2 phenotype and increased the levels of ECM proteins and α-SMA, which was abolished by NSC23766. In summary, Rac1 plays a crucial role in the pathogenesis of renal fibrosis after IR via regulation of expressions of profibrotic molecules, bone-marrow derived M2 macrophages recruitment, and M2 macrophages-myofibroblasts transition.
Agid:
6129123