Age Related Expression of Human AT1R Variants and Associated Renal Dysfunction in Transgenic Mice
Background: The contribution of single nucleotide polymorphisms in transcriptional regulation of the human angiotensin receptor type I (hAT1R) gene in age related chronic pathologies such as hypertension and associated renal disorders is not well known. The hAT1R gene has SNPs in its promoter that forms two haplotypes (Hap), Hap-I and Hap-II. Hap-I of AT1R gene is associated with hypertension in Caucasians. We have hypothesized here that age will alter the transcriptional environment of the cell and will regulate the expression of hAT1R gene in a haplotype-dependent manner. This could likely make subjects with Hap-I increasingly susceptible to age associated, AT1R mediated complications. Method: We generated transgenic (TG) mice with Hap-I and Hap-II. Adults (10-12 weeks) and aged (20-24 months) TG male mice containing either Hap-I or Hap-II were divided into four groups to study (a) the age associated and haplotype specific transcriptional regulation of hAT1R gene, and (b) their physiological relevance. Results: In aged animals, TG mice with Hap-I show increased expression of hAT1R and higher blood pressure; suppression of antioxidant defenses (HO1, SOD1) and antiaging molecules (ATRAP, Klotho, Sirt3); increased expression of pro-inflammatory markers (IL-6, TNF, CRP, NOX1); and increased insulin resistance. In vivo ChIP assay shows stronger binding of transcription factor USF2 to the chromatin of Hap-I mice. Conclusion: Our results suggest, that in aged animals, as compared to Hap-II, the TG mice with Hap-I over-express hAT1R gene due to the stronger transcriptional activity, thus resulting in an increase in their blood pressure and associated renal disorders.
Jain, S., Rana, A., Jain, K., Perla, S., Puri, N., & Kumar, A. (2018). Age Related Expression of Human AT1R Variants and Associated Renal Dysfunction in Transgenic Mice. American Journal of Hypertension, 31 (11), 1234-1242. https://doi.org/10.1093/ajh/hpy121