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Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

ABSTRACT: Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3?hours and increased further at 24?hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6?hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury.

SUBMITTER: Zhao SL

PROVIDER: S-EPMC5013493 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

Zhao Shi-Lei SL Wei Shi-Yao SY Wang Yu-Xiao YX Diao Tian-Tian TT Li Jian-Si JS He Yi-Xin YX Yu Jing J Jiang Xi-Yue XY Cao Yang Y Mao Xin-Yue XY Wei Qiu-Ju QJ Wang Yu Y Li Bing B

Scientific reports 20160907

Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological al ...[more]

PMID: 27600466

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Project description:BackgroundAcute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear.MethodsRenal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI.ResultHMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1β, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery.ConclusionThe present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI.

Project description:Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) play an important role in several pathogenic processes of the kidney. However, functions of lncRNAs in ischemic acute kidney injury (AKI) remain undefined. In this study, global lncRNA profiling indicated that many lncRNA transcripts were deregulated in kidney after ischemia reperfusion (IR). Among them, we identified IRAR (ischemia-reperfusion injury associated RNA) as a potential lncRNA candidate, which was mostly expressed by the tubular epithelial cells (TECs) after IR, involved in the development of AKI. GapmeR-mediated silencing and viral-based overexpression of IRAR were carried out to assess its function and contribution to IR-induced AKI. The results revealed that in vivo silencing of IRAR significantly reduced IR-induced proinflammatory cells infiltration and AKI. IRAR overexpression induced chemokine CCL2, CXCL1 and CXCL2 expression both in mRNA and protein levels in TECs, while, silencing of IRAR resulted in downregulation of these chemokines. RNA immunoprecipitation and RNA pulldown assay validated the association between IRAR and CCL2, CXCL1/2. Further examination revealed that specific ablation of CCL2 in TECs reduced macrophages infiltration and proinflammatory cytokine production, attenuated renal dysfunction in IR mice. Inhibition of CXC chemokine receptor 2 (receptor of CXCL1/2) reduced neutrofils infiltration, but had no overt effect on kidney function. To explore the mechanism of IRAR upregulation in kidney during IR, we analyzed promoter region of IRAR and predicted a potential binding site for transcription factor C/EBP β on IRAR promoter. Silencing of C/EBP β reduced IRAR expression in TECs. A dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) confirmed that IRAR was a transcriptional target of the C/EBP β. Altogether, our findings identify IRAR as a new player in the development of ischemic AKI through regulating chemokine production and immune cells infiltration, suggesting that IRAR is a potential target for prevention and/or attenuation of AKI.

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Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

Publications

Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

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