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-β 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.
Highlights
Progressive tubulointerstitial fibrosis (TIF) is the final common pathway leading to end stage renal disease, irrespective of the initial cause [1,2,3]
Yang et al reported that prolonged G2/M arrest of proximal tubular cells leads to overproduction of transform growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) [13]
To further decipher its localization in tubular epithelial cells (TECs), Numb was co-stained with megalin, a marker of proximal tubules, indicating that Numb is expressed in proximal tubules (Figure 1B)
Summary
Progressive tubulointerstitial fibrosis (TIF) is the final common pathway leading to end stage renal disease, irrespective of the initial cause [1,2,3]. It has been shown that the activation of NF-κB inflammatory signaling in tubular epithelial cells (TECs) triggers the production of inflammatory chemokines and cytokines, promotes interstitial inflammation [4]. Most recent studies demonstrate that partial epithelial to mesenchymal transition (EMT) of TECs is activated in the event of renal damage, and these damaged TECs relays signals to promote myofibroblast differentiation and fibrogenesis [12]. Genome-wide unbiased transcript analysis of human kidney samples revealed that defective fatty acid oxidation in TECs contributes to the development of TIF [14]. These findings suggest that TECs play a crucial role in the pathogenesis of TIF
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