Hypertensive Renal Injury Is Associated with Gene Variation Affecting Immune Signaling

Background— The spontaneously hypertensive rat (SHR) strain exists in lines that contrast strongly in susceptibility to renal injury in hypertension. These inbred lines share common ancestry, and only 13% of their genomes arise from different ancestors. Methods and Results— We used next gen sequencing to detect natural allelic variation in 5 genes of the immunoreceptor signaling pathway (IgH, Dok3, Src, Syk, and JunD) that arise from different ancestors in the injury-prone SHR-A3 and the resistant SHR-B2 lines. We created an intercross between these lines, and in the F2 progeny, we observed that the inheritance of haplotype blocks containing the SHR-A3 alleles of these 5 genes correlated with increased albuminuria and histological measures of renal injury. To test whether accumulated genetic variation in this pathway may create a therapeutic target in hypertensive renal injury, rats of both lines were treated with the immunosuppressant mycophenolate mofetil (MMF). MMF reduced proteinuria (albumin to creatinine ratio) from 6.6 to 1.2 mg/mg ( P <0.001) in SHR-A3. Glomerular injury scores were reduced in MMF-treated SHR-A3 from 1.6 to 1.4 ( P <0.002). Tubulo-interstitial injury was reduced in MMF-treated SHR-A3 from 2.62 to 2.0 ( P =0.001). MMF treatment also reduced renal fibrosis in SHR-A3 (3.9 versus 2.0; P <0.001). Conclusions— Polygenic susceptibility to renal injury in hypertension arises in association with genetic variation in genes that participate in immune responses and is dramatically improved by reduction of immune system activity.