title: Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models.
abstract: Podocyte injury and the appearance of proteinuria are features of minimal-change disease (MCD). Cyclosporin A (CsA) and tacrolimus (FK506) has been reported to reduce proteinuria in patients with nephrotic syndrome, but mechanisms remain unknown. We, therefore, investigated the protective mechanisms of CsA and FK506 on proteinuria in a rat model of MCD induced by puromycin aminonucleoside (PAN) and in vitro cultured mouse podocytes. Our results showed that CsA and FK506 treatment decreased proteinuria via a mechanism associated to a reduction in the foot-process fusion and desmin, and a recovery of synaptopodin and podocin. In PAN-treated mouse podocytes, pre-incubation with CsA and FK506 restored the distribution of the actin cytoskeleton, increased the expression of synaptopodin and podocin, improved podocyte viability, and reduced the migrating activities of podocytes. Treatment with CsA and FK506 also inhibited PAN-induced podocytes apoptosis, which was associated with the induction of Bcl-xL and inhibition of Bax, cleaved caspase 3, and cleaved PARP expression. Further studies revealed that CsA and FK506 inhibited PAN-induced p38 and JNK signaling, thereby protecting podocytes from PAN-induced injury. In conclusion, CsA and FK506 inhibit proteinuria by protecting against PAN-induced podocyte injury, which may be associated with inhibition of the MAPK signaling pathway.
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Xiujin
authors: X
authors: Shen
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Hong
authors: H
authors: Jiang
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Meike
authors: M
authors: Ying
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Zhoutao
authors: Z
authors: Xie
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Xiayu
authors: X
authors: Li
authors: National Clinical Research Base of Traditional Chinese Medicine, Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
authors: Haibing
authors: H
authors: Wang
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Jie
authors: J
authors: Zhao
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Chuan
authors: C
authors: Lin
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Yucheng
authors: Y
authors: Wang
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Shi
authors: S
authors: Feng
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Jia
authors: J
authors: Shen
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Chunhua
authors: C
authors: Weng
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Weiqiang
authors: W
authors: Lin
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Huiping
authors: H
authors: Wang
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Qin
authors: Q
authors: Zhou
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Yan
authors: Y
authors: Bi
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Meng
authors: M
authors: Li
authors: Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China.
authors: Lingyan
authors: L
authors: Wang
authors: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors: Tongyu
authors: T
authors: Zhu
authors: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
authors: Xiaoru
authors: X
authors: Huang
authors: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
authors: Hui-Yao
authors: HY
authors: Lan
authors: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
authors: Jing
authors: J
authors: Zhou
authors: Kidney Disease Center, First Affiliated Hospital, Zhejiang University, School of Medicine; Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, Zhejiang, China.
authors: Jianghua
authors: J
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D065095:Calcineurin Inhibitors; D002460:Cell Line; D016572:Cyclosporine / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009402:Nephrosis, Lipoid / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011507:Proteinuria / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D011692:Puromycin Aminonucleoside / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000008:administration & dosage*
chemical_list: D065095:Calcineurin Inhibitors; D011692:Puromycin Aminonucleoside; D016572:Cyclosporine; D016559:Tacrolimus