Numb contributes to renal fibrosis by promoting tubular epithelial cell cycle arrest at G2/M

// Fengxin Zhu 1 , Wei Liu 2 , Tang Li 3 , Jiao Wan 1 , Jianwei Tian 1 , Zhanmei Zhou 1 , Hao Li 1 , Youhua Liu 1 , Fan Fan Hou 1 , Jing Nie 1 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China 2 Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, P.R. China 3 The VIP Medical Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China Correspondence to: Jing Nie e-mail: niejing@smu.edu.cn Keywords: Numb, G2/M arrest, p53, proximal tubular cells, interstitial fibrosis Received: November 30, 2015      Accepted: March 06, 2016      Published: March 21, 2016 ABSTRACT Numb is a multifunctional protein involved in diverse cellular processes. However, the function of Numb in kidney remains unclear. Here, we reported that Numb is expressed in renal tubules and glomeruli in normal adult kidney. Numb expression was upregulated in fibrotic kidneys induced by unilateral ureteral obstruction (UUO) in mice as well as in human fibrotic kidney tissues. Numb overexpression in cultured proximal tubular cells increased the G2/M cell population and upregulated the expression of TGF-β1 and CTGF. Whereas, proximal tubule Numb knockout (PEPCK-Numb-KO) mice showed reduced G2/M arrest, decreased expression of TGF-β1 and CTGF, and attenuated fibrotic lesions due to either UUO or unilateral ischemia reperfusion nephropathy. Inhibiting p53 activity by pifithrin-` dramatically mitigated Numb-induced G2/M arrest, indicating that Numb potentiates G2/M arrest via stabilizing p53 protein. Together, these data suggest that Numb is a potential target for anti-fibrosis therapy.