Genetic variants in Arhgef11 are associated with kidney injury in the Dahl salt-sensitive rat. Hypertension 2012 Nov;60(5):1157-68
Date
09/19/2012Pubmed ID
22987919Pubmed Central ID
PMC3505884DOI
10.1161/HYPERTENSIONAHA.112.199240Scopus ID
2-s2.0-84868200082 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
A previous genetic analysis comparing the Dahl salt-sensitive (S) rat with the spontaneously hypertensive rat identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective spontaneously hypertensive rat genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared with the S. The causative locus interval was narrowed to <375 kb on the basis of congenic strains, haplotype data, comparative mapping, and concordance with human genetic studies. Sequencing of the coding region of genes in this region identified 36 single nucleotide polymorphisms (13 nonsynonymous and 23 synonymous). Gene expression profiling indicated that only a few genes exhibited differential expression. Arhgef11, Pear1, and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared with untreated S). However, no difference was observed between treated or untreated spontaneously hypertensive rat or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate in the Candidate Gene Association Resource population. In summary, these findings demonstrate that allelic variants in Arhgef11, acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.
Author List
Williams JM, Johnson AC, Stelloh C, Dreisbach AW, Franceschini N, Regner KR, Townsend RR, Roman RJ, Garrett MRAuthor
Kevin R. Regner MD Interim Chair, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
1-(5-Isoquinolinesulfonyl)-2-MethylpiperazineAnimals
Animals, Congenic
Blood Pressure
Blotting, Western
Chromosome Mapping
Gene Expression Profiling
Genetic Predisposition to Disease
Guanine Nucleotide Exchange Factors
Humans
Kidney
Kidney Diseases
Male
Polymorphism, Single Nucleotide
Protein Kinase Inhibitors
Proteinuria
Quantitative Trait Loci
Rats
Rats, Inbred Dahl
Rats, Inbred SHR
Renal Circulation
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
rho-Associated Kinases
rhoA GTP-Binding Protein
