title: 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-α. TGF-α 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-α 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.
authors.affiliation: INSERM U845, Université Paris Descartes, Team: Mechanisms and therapeutic strategies in chronic nephropathies, Hôpital Necker Enfants Malades, Tour Lavoisier, 6ème étage, 149 Rue de Sèvres, 75015 Paris, France.
authors.forename: Denise
authors.initials: D
authors.lastname: Laouari
authors.forename: Martine
authors.initials: M
authors.lastname: Burtin
authors.forename: Aurélie
authors.initials: A
authors.lastname: Phelep
authors.forename: Carla
authors.initials: C
authors.lastname: Martino
authors.forename: Evangeline
authors.initials: E
authors.lastname: Pillebout
authors.forename: Xavier
authors.initials: X
authors.lastname: Montagutelli
authors.forename: Gérard
authors.initials: G
authors.lastname: Friedlander
authors.forename: Fabiola
authors.initials: F
authors.lastname: Terzi
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002908:Chronic Disease; D020022:Genetic Predisposition to Disease; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D009399:Nephrons / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D016211:Transforming Growth Factor alpha