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TGF-alpha mediates genetic susceptibility to chronic kidney disease.


ABSTRACT: The mechanisms of progression of chronic kidney disease (CKD) are poorly understood. Epidemiologic studies suggest a strong genetic component, but the genes that contribute to the onset and progression of CKD are largely unknown. Here, we applied an experimental model of CKD (75% excision of total renal mass) to six different strains of mice and found that only the FVB/N strain developed renal lesions. We performed a genome-scan analysis in mice generated by back-crossing resistant and sensitive strains; we identified a major susceptibility locus (Ckdp1) on chromosome 6, which corresponds to regions on human chromosome 2 and 3 that link with CKD progression. In silico analysis revealed that the locus includes the gene encoding the EGF receptor (EGFR) ligand TGF-?. TGF-? protein levels markedly increased after nephron reduction exclusively in FVB/N mice, and this increase preceded the development of renal lesions. Furthermore, pharmacologic inhibition of EGFR prevented the development of renal lesions in the sensitive FVB/N strain. These data suggest that variable TGF-? expression may explain, in part, the genetic susceptibility to CKD progression. EGFR inhibition may be a therapeutic strategy to counteract the genetic predisposition to CKD.

SUBMITTER: Laouari D 

PROVIDER: S-EPMC3029905 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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TGF-alpha mediates genetic susceptibility to chronic kidney disease.

Laouari Denise D   Burtin Martine M   Phelep Aurélie A   Martino Carla C   Pillebout Evangeline E   Montagutelli Xavier X   Friedlander Gérard G   Terzi Fabiola F  

Journal of the American Society of Nephrology : JASN 20101223 2


The mechanisms of progression of chronic kidney disease (CKD) are poorly understood. Epidemiologic studies suggest a strong genetic component, but the genes that contribute to the onset and progression of CKD are largely unknown. Here, we applied an experimental model of CKD (75% excision of total renal mass) to six different strains of mice and found that only the FVB/N strain developed renal lesions. We performed a genome-scan analysis in mice generated by back-crossing resistant and sensitive  ...[more]

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