| First Author | Laouari D | Year | 2011 |
| Journal | J Am Soc Nephrol | Volume | 22 |
| Issue | 2 | Pages | 327-35 |
| PubMed ID | 21183591 | Mgi Jnum | J:185880 |
| Mgi Id | MGI:5430455 | Doi | 10.1681/ASN.2010040356 |
| Citation | Laouari D, et al. (2011) TGF-alpha mediates genetic susceptibility to chronic kidney disease. J Am Soc Nephrol 22(2):327-35 |
| abstractText | 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-alpha. TGF-alpha 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-alpha 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. |
