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Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells

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Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells BASIC RESEARCH www.jasn.org Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells Congwei Luo,1 Shan Zhou,1 Zhanmei Zhou,1 Yahong Liu,1 Li Yang,1 Jiafeng Liu,1 Yunfang Zhang,2 Hongyan Li,2 Youhua Liu ,1,3 Fan Fan Hou,1 and Lili Zhou1 1State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital and 2Department of Nephrology, Huadu District People’s Hospital, Southern Medical University, Guangzhou, China; and 3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania ABSTRACT Cellular senescence is associated with renal disease progression, and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. However, the underlying mechanism is unknown. We assessed the potential role of Wnt9a in tubular cell senescence and renal fibrosis. Compared with tubular cells of normal subjects, tubular cells of humans with a variety of nephropathies and those of several mouse models of CKD expressed high levels of Wnt9a that colocalized with the senescence-related protein p16INK4A. Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and ex- pression of p16INK4A. Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of b-catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16INK4A expression and senescence-associated b-galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis in vivo and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a- induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A in the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16INK4A,p19ARF, p53, and p21 and decreased the phosphorylation of ret- inoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF-b1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a–TGF-b pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the path- ogenesis of renal fibrosis. J Am Soc Nephrol 29: 1238–1256, 2018. doi: https://doi.org/10.1681/ASN.2017050574 CKD is highly prevalent worldwide, especially in the 1 elderly. Compared with younger counterparts, the Significance Statement elderly have higher rates of CKD, and mortality and CKD displays a number of features of accelerated se- nescence. Specifically, tubular cell senescence is Received May 25, 2017. Accepted January 3, 2018. strongly associated with progression of renal fibrosis. However, the underlying mechanisms of tubular se- Published online ahead of print. Publication date available at nescence are poorly understood. This study examines www.jasn.org. the potential role of Wnt9a in tubular cell senescence fi Correspondence: Dr. Lili Zhou or Dr. Fan Fan Hou, Division of and renal brosis in human biopsy material and in ex- Nephrology, Nanfang Hospital, Southern Medical University, perimental models. The authors found that Wnt9a 1838 North Guangzhou Avenue, Guangzhou 510515, China. knockdown in vivo with shRNA suppressed fibrosis, E-mail: [email protected] or [email protected] suggesting a decisive role for this pathway in tubular senescence and fibroblast activation. Copyright © 2018 by the American Society of Nephrology 1238 ISSN : 1046-6673/2904-1238 JAmSocNephrol29: 1238–1256, 2018 www.jasn.org BASIC RESEARCH renal function decline are worse in older than in younger pa- RESULTS tients.1,2 Interestingly, CKD-affected kidneys have many char- acteristics associated with natural aging, such as glomerular Wnt9a Increases in Multiple Types of Clinical sclerosis and interstitial fibrosis,3 tubular atrophy,4 local re- Nephropathy and Experimental CKD Models and nin-angiotensin-aldosterone system activation,5 loss of repair Associates with Tubular Senescence capabilities6 in renal tubular cells, and intracellular deposition Totest the clinical relevance of Wnt ligands in the pathogenesis of lipofuscin, a strong indicator of senescence.7,8 These find- of CKD, we conducted immunostaining in kidney biopsy ings suggest CKD is a clinical manifestation of premature ag- specimens from 35 patients with various nephropathies, ing or accelerated senescence.9 including minimal change disease, IgA nephropathy (IgAN), Cellular senescence, a stress-induced growth arrest, has re- diabetic nephropathy, membranous nephropathy, lupus ne- cently been found in multiple kidney diseases2,7,10,11 and tu- phritis, and others. Most of these diseases are highly associated bulointerstitial nephritis.11 The accumulation of senescent with accelerated cellular senescence.4,11,12 Compared with the cells has been detected in early clinical nephropathy, when absence of signal in normal human kidneys, the signal for patients have mild proteinuria and normal GFR.4,10 Accelera- Wnt9a strikingly increased in all biopsy specimens from pa- ted senescence may promote more pathologic alterations in tients with CKD (Figure 1A). Notably, Wnt9a was predomi- kidneys7,8,12 and even reduce the healthy lifespan.13 nantly localized in the renal tubular epithelium in human The key characteristics of cellular senescence are growth diseased kidneys (Figure 1A, arrows). Furthermore, immu- arrest and loss of DNA replication, breakdown of DNA double nostaining on sequential sections of human IgAN biopsy spec- strands,14 and accumulation of senescence-related proteins imens confirmed the localization of Wnt9a in tubular cells mainly through p16INK4A-retinoblastoma (Rb) and ARF- with Ki67-negative nuclei, a feature of senescent cells (Figure p53-p21 pathways.15,16 These pathways collectively halt cell 1B, yellow arrows).14 Because p16INK4A is also a typical senes- proliferation and accelerate cellular senescence. Senescent cence-related protein marker,13 we examined the colocaliza- cells can be identified by senescence-associated b-galactosidase tion of Wnt9a and p16INK4A expression. As shown in Figure (SA–b-gal) activity,4,13 and these cells produce components of 1C, the expression of Wnt9a nearly completely colocalized the senescence-associated secretory phenotype (SASP), includ- with p16INK4A-positive tubules. Furthermore, among 30 pa- ing proinflammatory cytokines such as IL-6 and matrix-syn- tients with sequentially sectioned biopsy specimens available thesizing molecules such as TGF-b1.17,18 for additional analysis, there was a positive correlation be- Cellular senescence can be caused by DNA damage, mito- tween Wnt9a and p16INK4A expression levels (Figure 1D). Ad- chondria dysfunction, inflammation, oxidative stress, and epi- ditionally, Wnt9a expression correlated with renal fibrosis and genetic alterations, each of which is a common characteristic decline of eGFR (Figure 1, E and F). The demographic and feature in CKD.4,13,19,20 Of note, among somatic cells of the clinical data of the patients with CKD are presented in Sup- kidney, tubular cells are the most likely to transition to the se- plemental Table 1. nescent phenotype.4,10,11,21 However, the underlying molecular To further evaluate the role of Wnt9a in tubular senescence mechanism of tubular senescence has not been elucidated. and progression of CKD, we assessed the expression of Wnt9a in Wnt/b-catenin signaling is an evolutionarily conserved different CKD models, including mice subjected to ischemia- pathway involved in organ development and tissue repair.6 reperfusion injury (IRI), unilateral ureteral obstruction (UUO), In normal adults, Wnt/b-catenin signaling is silent, but it is andadriamycin (ADR)nephropathy. AsshowninFigure 2, Aand reactivated after kidney injury in a wide range of CKD mod- B, Wnt9a expression increased as early as 1 day after severe IRI, els.5,22,23 Recent publications show the aberrant expression of although this increase was not yet significant. Three days after Wnt/b-catenin is highly associated with progression of renal severe IRI, the key transitional time point at which AKI prog- fibrosis5,23 and tubular atrophy.3 Such pathologic effects may resses to CKD through sustained activation of Wnt(s) signal- result from increased hyperactivity of local renin-angiotensin- ing,24 Wnt9a expression was significantly upregulated, as was the aldosterone system5 and repressed expression of Klotho, an expression of histone gH2AX. gH2AX is a selective marker of antiaging protein,22 caused by the increase in Wnt/b-catenin DNA double-strand breaks, and an increase in the number of signaling. These findings suggest the intimate correlation be- gH2AX foci is an important feature of senescence.25,26 We also tween Wnt activation and cellular senescence. However, whether assessed the expression of the antiaging protein Klotho, the loss Wnt ligands directly promote renal tubular cell senescence and of which derepresses Wnt signaling and serves as a marker of the progression of renal fibrosis remains unknown. tubular damage and CKD.22 As shown in Figure 2, A and C, as In this study, we examined the role of Wnt9a in CKD- Wnt9a expression increased after IRI, Klotho expression corre- associated renal fibrosis and tubular senescence in vivo and spondingly decreased. We then checked
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