Braun Michael C, Herring Stacy M, Gokul Nisha, Monita Monique, Bell Rebecca, Zhu Yaming, Gonzalez-Garay Manuel L, Wenderfer Scott E, Doris Peter A
From the Department of Pediatrics, Baylor College of Medicine (M.C.B., S.E.W.), and Institute of Molecular Medicine (S.M.H., N.G., M.M., R.B., Y.Z., M.L.G.-G., P.A.D.), University of Texas Health Science Center at Houston.
Circ Cardiovasc Genet. 2014 Dec;7(6):903-10. doi: 10.1161/CIRCGENETICS.114.000533. Epub 2014 Nov 3.
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.
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).
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.
自发性高血压大鼠（SHR）品系存在对高血压肾损伤易感性差异很大的品系。这些近交系有共同的祖先，其基因组中只有13%来自不同的祖先。
我们使用二代测序检测免疫受体信号通路5个基因（IgH、Dok3、Src、Syk和JunD）中的自然等位基因变异，这些基因来自易损伤的SHR - A3品系和抗性SHR - B2品系的不同祖先。我们将这些品系进行杂交，在F2代后代中，我们观察到包含这5个基因SHR - A3等位基因的单倍型块的遗传与蛋白尿增加和肾损伤的组织学指标相关。为了测试该通路中积累的基因变异是否可能成为高血压肾损伤的治疗靶点，两个品系的大鼠均用免疫抑制剂霉酚酸酯（MMF）治疗。MMF使SHR - A3的蛋白尿（白蛋白与肌酐比值）从6.6降至1.2 mg/mg（P<0.001）。MMF治疗的SHR - A3的肾小球损伤评分从1.6降至1.4（P<0.002）。MMF治疗的SHR - A3的肾小管间质损伤从2.62降至2.0（P = 0.001）。MMF治疗还减轻了SHR - A3的肾纤维化（3.9对2.0；P<0.001）。
高血压肾损伤的多基因易感性与参与免疫反应的基因的遗传变异有关，通过降低免疫系统活性可显著改善。
