Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Abstract

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, uACR) 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 vs. 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.

Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus

“…29,31,55 The approximately 87% of the genome shared identical by descent across these lines is partitioned into discrete haplotype blocks. 55 An F2 intercross was generated by crossing male SHR-A3 and female SHR-B2 animals and further crossing the resulting F1 progeny, as previously described, 56 and was used to test the association between inheritance of Stim1 alleles and urine creatinine. Animals were provided a standard rodent chow diet and drinking water ad libitum unless subjected to 24-hour water deprivation test in metabolic cages using established protocols.…”

Susceptibility to Hypertensive Renal Disease in the Spontaneously Hypertensive Rat Is Influenced by 2 Loci Affecting Blood Pressure and Immunoglobulin Repertoire

“…Our prior work indicates that difference in injury susceptibility appears to result, at least in part, from genetic variation in SHR-A3 that influences renal inflammation 12 . This raises the question of whether substitution of the chr17 block affecting SBP and renal injury alters an immune component of renal injury in SHR-A3.…”

“…Because administration of an immunosuppressive drug (mycophenolate mofetil) that impedes proliferation and maturation of T and B lymphocytes also reduces renal injury in SHR-A3 12 , we considered it possible that IgH variation might provide a genetic influence on renal injury in SHR-A3. Figure 3 shows that glomerular injury is reduced at 40 weeks of age in the SHR-A3(IgH SHR-B2) line and approaches levels observed in SHR-B2 (SHR-A3 = 1.91 ± 0.08, SHR-A3(IgH SHR-B2) = 1.36 ± 0.08 and SHR-B2 1.20 ± 0.07).…”

“…We have previously described the assembly and analysis of Illumina short-read genome sequences from SHR-A3 and SHR-B2 12 . Variant call files are available on request to the corresponding author.…”

“…Much normal tissue architecture remains between focal regions of injury and disease progression includes both increasing severity of injury in injury foci and increased numbers of injury foci 11 . The close genetic similarity between these lines (87% identical by descent, IBD) provides an opportunity to discover and prove the genetic basis of this susceptibility 12 .…”