Numb Induces E-Cadherin Adhesion Dissolution, Cytoskeleton Reorganization, and Migration in Tubular Epithelial Cells Contributing to Renal Fibrosis

Ding, Xiuhua; Ma, Mingming; Teng, Jie; Shao, Fengmin; Teng, Robert K. F.; Zhou, Shuang; Zhang, Y.; Wu, Erxi; Wang, X.

doi:10.2174/1566524015666150505162015

Cited by 12 publications

(16 citation statements)

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“…Numb protein, involved in protein endocytosis [Dho et al, 2006], selectively binds to certain transmembrane receptors and links them to endocytosis for receptors internalization [Nishimura and Kaibuchi, 2007]. Our recent study suggests that overexpression of Numb enhanced integrin endocytosis in PTCs [Ding et al, 2015]. Taken together, these results suggest that Numb plays a role on albumin endocytosis in PTCs.…”

Section: Discussionmentioning

confidence: 84%

Numb Protects Human Renal Tubular Epithelial Cells From Bovine Serum Albumin‐Induced Apoptosis Through Antagonizing CHOP/PERK Pathway

Ding

Teng

et al. 2015

J of Cellular Biochemistry

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In recent studies, we found that Numb is involved in oxidative stress-induced apoptosis of renal proximal tubular cells; however, its function on ER stress-induced apoptosis in proteinuric kidney disease remains unknown. The objective of the present study is to explore the role of Numb in urinary albumin-induced apoptosis of human renal tubular epithelial cells (HKCs). In this study, we demonstrate that incubation of HKCs with bovine serum albumin (BSA) resulted in caspase three-dependent cell death. Numb expression was down-regulated by BSA in a time- and dose-dependent manner. Knockdown of Numb by siRNA sensitized HKCs to BSA-induced apoptosis, whereas overexpression of Numb protected HKCs from BSA-induced apoptosis. Moreover, BSA activated CHOP/PERK signaling pathway in a time- and dose-dependent manner as indicated by increased expression of CHOP, PERK, and P-PERK. Furthermore, knockdown of CHOP or PERK significantly attenuated the promoting effect of Numb on BSA-induced apoptosis, while overexpression of CHOP impaired the protective effect of Numb on BSA-induced apoptosis. Taken together, our findings demonstrate that Numb plays a protective role on BSA-induced apoptosis through inhibiting CHOP/PERK signaling pathway in human renal tubular epithelial cells. Therefore, the results from this study provides evidence that Numb is a new target of ER-associated apoptotic signaling networks and Numb may serve as a promising therapeutic target for proteinuric diseases.

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Section: Discussionmentioning

confidence: 84%

Numb Protects Human Renal Tubular Epithelial Cells From Bovine Serum Albumin‐Induced Apoptosis Through Antagonizing CHOP/PERK Pathway

Ding

Teng

et al. 2015

J of Cellular Biochemistry

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“…Long-term PD is limited due to the morphological and functional changes of the peritoneum induced by PD fluids, which contain high concentrations of glucose that eventually lead to ultrafiltration failure (1). Epithelial-mesenchymal transition (EMT) is involved in the fibrosis of various organs, including renal fibrosis, liver fibrosis and peritoneal fibrosis (2)(3)(4). High glucose (HG)-induced EMT of human peritoneal mesothelial cells (HPMCs) may be a key process in the fibrosis and dysfunction of the peritoneal membrane (5).…”

Section: Introductionmentioning

confidence: 99%

1,25(OH)2D3/VDR attenuates high glucose-induced epithelial-mesenchymal transition in human peritoneal mesothelial cells via the TGFβ/Smad3 pathway

Yang

Zhang

et al. 2017

Molecular Medicine Reports

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Epithelial-mesenchymal transition (EMT) has been recognized to accelerate peritoneal membrane dysfunction. 1,25(OH)2D3/vitamin D receptor (VDR) is important for preventing various types of EMT in vivo. However, its function on EMT and inflammation of human peritoneal mesothelial cells (HPMCs) remains to be elucidated. Therefore, the present study investigated the effects of 1,25(OH)2D3/VDR on high glucose (HG)‑induced EMT and inflammation in HPMCs and the underlying molecular mechanism. It was determined that HG reduced VDR expression, increased inflammatory cytokine expression, including transforming growth factor β (TGFβ) and interleukin‑6 (IL‑6) and phosphorylated‑SMAD family member 3 (p‑Smad3) expression. EMT was promoted as the expression level of the epithelial marker E‑cadherin was reduced, whereas expression levels of the mesenchymal markers α‑SMA and FN were increased. 1,25(OH)2D3 pretreatment inhibited the expression of inflammatory cytokines in HPMCs and attenuated HG‑induced EMT, possibly through inhibition of the TGFβ/Smad pathway by binding to its receptor VDR.

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“…Although TGF-b1 activates p53, the mechanism is complex, involving increases in both MDM2 and the p53 stabilizing factor Numb (85)(86)(87)(88)(89). TGF-b1 stimulates Numb expression in proximal tubular cells, and Numb is elevated in the fibrotic kidney.…”

Section: Involvement Of P53 In Renal Diseasementioning

confidence: 99%

“…Adenoviral-mediated Numb delivery up-regulates p21 and TGF-b1-CTGF expression, increases p53 and p-p53 levels, and promotes G 2 /M stalling (89). G 2 /M arrest, transcription of profibrotic genes, and the extent of fibrogenesis are reduced in proximal tubule Numb-deficient mice following UUO or ischemia/reperfusion injury (88,89). Pifithrin-a attenuates Numb-induced G 2 /M arrest (89), suggesting the involvement of p53.…”

Section: Involvement Of P53 In Renal Diseasementioning

confidence: 99%

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

et al. 2019

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Chronic kidney disease affects >15% of the U.S. population and >850 million individuals worldwide. Fibrosis is the common outcome of many chronic renal disorders and, although the etiology varies (i.e., diabetes, hypertension, ischemia, acute injury, and urologic obstructive disorders), persistently elevated renal TGF‐β1 levels result in the relentless progression of fibrotic disease. TGF‐β1 orchestrates the multifaceted program of renal fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery and redifferentiation, and subsequent tubulointerstitial fibrosis, eventually leading to chronic renal disease. Recent findings implicate p53 as a cofactor in the TGF‐β1‐induced signaling pathway and a transcriptional coregulator of several TGF‐β1 profibrotic response genes by complexing with receptor‐activated SMADs, which are homologous to the small worms (SMA) and Drosophilia mothers against decapentaplegic (MAD) gene families. The cooperative p53‐TGF‐β1 genomic cluster includes genes involved in cell growth control and extracellular matrix remodeling [e.g., plasminogen activator inhibitor‐1 (PAI‐1; serine protease inhibitor, clade E, member 1), connective tissue growth factor, and collagen I]. Although the molecular basis for this codependency is unclear, many TGF‐β1‐responsive genes possess p53 binding motifs. p53 up‐regulation and increased p53 phosphorylation; moreover, they are evident in nephrotoxin‐ and ischemia/reperfusion‐induced injury, diabetic nephropathy, ureteral obstructive disease, and kidney allograft rejection. Pharmacologic and genetic approaches that target p53 attenuate expression of the involved genes and mitigate the fibrotic response, confirming a key role for p53 in renal disorders. This review focuses on mechanisms whereby p53 functions as a transcriptional regulator within the TGF‐β1 cluster with an emphasis on the potent fibrosis‐promoting PAI‐1 gene.—Higgins, C. E., Tang, J., Mian, B. M., Higgins, S. P., Gifford, C. C., Conti, D. J., Meldrum, K. K., Samarakoon, R., Higgins, P. J. TGF‐β1‐p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications. FASEB J. 33, 10596–10606 (2019). http://www.fasebj.org

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Numb Induces E-Cadherin Adhesion Dissolution, Cytoskeleton Reorganization, and Migration in Tubular Epithelial Cells Contributing to Renal Fibrosis

Cited by 12 publications

References 0 publications

Numb Protects Human Renal Tubular Epithelial Cells From Bovine Serum Albumin‐Induced Apoptosis Through Antagonizing CHOP/PERK Pathway

Numb Protects Human Renal Tubular Epithelial Cells From Bovine Serum Albumin‐Induced Apoptosis Through Antagonizing CHOP/PERK Pathway

1,25(OH)2D3/VDR attenuates high glucose-induced epithelial-mesenchymal transition in human peritoneal mesothelial cells via the TGFβ/Smad3 pathway

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

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