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Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis.

ABSTRACT: Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified an Src family tyrosine kinase, hematopoietic cell kinase (Hck), as upregulated in allografts in CAI. Querying the Kinase Inhibitor Resource database revealed that dasatinib, a Food and Drug Administration-approved drug, potently binds Hck with high selectivity. In vitro, Hck overexpression activated the TGF-?/Smad3 pathway, whereas HCK knockdown inhibited it. Treatment of tubular cells with dasatinib reduced the expression of Col1a1 Dasatinib also reduced proliferation and ?-SMA expression in fibroblasts. In a murine model with unilateral ureteric obstruction, pretreatment with dasatinib significantly reduced the upregulation of profibrotic markers, phosphorylation of Smad3, and renal fibrosis observed in kidneys pretreated with vehicle alone. Dasatinib treatment also improved renal function, reduced albuminuria, and inhibited expression of profibrotic markers in animal models with lupus nephritis and folic acid nephropathy. These data suggest that Hck is a key mediator of renal fibrosis and dasatinib could be developed as an antifibrotic drug.

SUBMITTER: Wei C

PROVIDER: S-EPMC5407716 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis.

Wei Chengguo C Li Li L Menon Madhav C MC Zhang Weijia W Fu Jia J Kidd Brian B Keung Karen L KL Woytovich Christopher C Greene Ilana I Xiao Wenzhen W Salem Fadi F Yi Zhengzi Z He John Cijiang JC Dudley Joel T JT Murphy Barbara B

Journal of the American Society of Nephrology : JASN 20161207 5

Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified an <i>Src</i> family tyrosine kinase, hematopoietic cell kinase (<i>Hck</i>), as upregulated in allografts in CAI. Querying the Kinase Inhibitor Res ...[more]

PMID: 27927780

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Project description:BackgroundNowadays, renal allograft survival is confined by the development of allograft fibrosis. Previous studies have reported interleukin-33 (IL-33) upregulated significantly in patients with chronic renal allograft dysfunction, and it could induce renal tubular epithelial to mesenchymal transition (EMT), which eventually contributed to renal allograft fibrosis. Our study intended to detect the underlying association between single nucleotide polymorphisms (SNPs) of IL-33 gene and renal allograft fibrosis in kidney transplant recipients.MethodsWe collected blood samples from 200 renal transplant recipients for the identification of SNPs and transplanted kidney tissue samples for identifying differentially expressed genes (DEGs). Intersection of SNP-related genes and DEGs was conducted for further analysis. Relationships between these SNPs and renal allograft fibrosis were evaluated by the inheritance models. Immunohistochemical (IHC) staining and western blotting (WB) were used to detect the expression of IL-33 and the markers of EMT in human kidney tissues obtained from control and chronic renal allograft dysfunction (CAD) patients. In vitro, we detected the progressions of EMT-related markers and the levels of MAPK signaling pathway mediators after transfecting IL-33 mutant plasmids in HK2 cells.ResultsThree intersected genes including IL-33 genes were significantly expressed. IL-33 expression was validated in kidney tissues by IHC and WB. Thirty-nine IL-33-related SNPs were identified in targeted sequencing, in which 26 tagger SNPs were found by linkage disequilibrium analysis for further analysis. General linear models indicated sirolimus administration significantly influenced renal allograft fibrosis (P < 0.05), adjustment of which was conducted in the following analysis. By multiple inheritance model analyses, SNP rs10975519 of IL-33 gene was found closely related to renal allograft fibrosis (P < 0.005). Furthermore, HK2 cells transfected with mutated plasmid of rs10975519 showed stronger mobility and migration ability. Moreover, IL-33 mutant plasmids could promote the IL-33-induced EMT through the sustained activation of p38 MAPK signaling pathway in HK2 cells.ConclusionIn our study, rs10975519 on the IL-33 gene was found to be statistically associated with the development of renal allograft fibrosis in kidney transplant recipients. This process may be related to the IL-33-induced EMT and sustained activation of p38 MAPK signaling pathway.

Dataset Information

Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis.

Publications

Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis.

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