Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling.
Kindlin-2 is an adaptor protein that contributes to renal tubulointerstitial fibrosis (TIF). Epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells was regarded as one of the key events in TIF. To determine whether kindlin-2 is involved in the EMT process, we investigated its regulation of EMT in human kidney tubular epithelial cells (TECs) and explored the underlying mechanism. In this study, we found that overexpression of kindlin-2 suppressed epithelial marker E-cadherin and increased the expression of fibronectin and the myofibroblast marker α-smooth muscle actin (SMA). Kindlin-2 significantly activated ERK1/2 and Akt, and inhibition of ERK1/2 or Akt reversed kindlin-2-induced EMT in human kidney TECs. Mechanistically, kindlin-2 interacted with Ras and son of sevenless (Sos)-1. Furthermore, overexpression of kindlin-2 increased Ras activation through recruiting Sos-1. Treatment with a Ras inhibitor markedly repressed kindlin-2-induced ERK1/2 and Akt activation, leading to restraint of EMT. We further demonstrated that knockdown of kindlin-2 inhibited EGF-induced Ras-Sos-1 interaction, resulting in reduction of Ras activation and suppression of EMT stimulated by EGF. Importantly, we found that depletion of kindlin-2 significantly inhibited activation of ERK1/2 and Akt signaling in mice with unilateral ureteral obstruction. We conclude that kindlin-2, through activating Ras and the downstream ERK1/2 and Akt signaling pathways, plays an important role in regulating renal tubular EMT and could be a potential therapeutic target for the treatment of fibrotic kidney diseases.
Laboratory of Molecular Cell Biology and Tumor Biology, Dept. of Anatomy, Histology, and Embryology, Peking Univ. Health Science Center, No. 38 Xue Yuan Rd., Beijing 100191, China. Hongquan.Zhang@bjmu.edu.cn.
Xiaofan
X
Wei
Xiang
X
Wang
Yang
Y
Xia
Yan
Y
Tang
Feng
F
Li
Weigang
W
Fang
Hongquan
H
Zhang
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005455:Fluorescent Antibody Technique; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007684:Kidney Tubules / Q000166:cytology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D009395:Nephritis, Interstitial / Q000503:physiopathology; D051058:Oncogene Protein v-akt / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020837:SOS1 Protein / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014517:Ureteral Obstruction / Q000503:physiopathology
D003598:Cytoskeletal Proteins; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D020837:SOS1 Protein; C527802:kindlin-2 protein, mouse; D051058:Oncogene Protein v-akt
Ras signaling; kindlin-2; tubular cell plasticity