Post doc fellow New York Medical College Valhalla, New York, United States
Harshada Ketkar (New York Medical College)| Samantha Tang (New York Medical College)| Ashok Kumar (New York Medical College)| Sudhir Jain (New York Medical College)
Human AT1R over-expression may cause pathological outcomes due to renin-angiotensin system overactivity. We have shown that transgenic (TG) mice containing Hap-I (hypertensive genotype) of human AT1 receptor type 2 (hAT1R) gene are more prone to develop metabolic syndrome disorders as compared to TG mice with Hap-II (normotensive genotype). This increased risk of hypertension together with aging and Western diet may lead to multiple renal disorders. However, mechanisms underlying this process is still not well examined. For this purpose, we studied the gene expression profile alterations in kidneys of aged TG mice containing Hap-I and Hap-II of hAT1R gene. Aged mice (20-24 months of age) were maintained on a regular diet or high fat diet with 2% NaCl (Western diet) for 16 weeks. Blood pressure was monitored by telemetry, whereas renal morphology and gene expression profile were established using histological and RNA-seq analysis, respectively. On regular diet, aged Hap-I mice presented higher (~9 mmHg) systolic blood pressure with respect to age-matched Hap-II animals. Following administration of Western diet, blood pressure increased in both groups of mice, but to a larger extent in Hap-I animals (~15 mmHg in comparison to ~7 mmHg in Hap-II). Aged Hap-I mice on Western diet showed increased renal fibrosis. RNA-seq data from renal tissue of Hap-I aged mice revealed that Western diet significantly altered the expression of >400 genes (p-adj. <0.05). Bioinformatics analysis utilizing Qiagen IPA software identified major alterations in main canonical pathways involved in renal function and oxidative damage. These in turn cause kidney failure, renal tubular injury and renal proliferation. Importantly, SNCA, IL10RA, dexamethasone, LPS and TNF were among the top upstream regulators significantly affected by Western diet. Overall, these results indicate that Western diet promotes hypertension and fibrosis in the kidneys of aged mice. These alterations are paralleled by perturbation of renal transcriptional profile. These studies will assist in the identification of novel molecules and mechanisms involved in hypertension and associated kidney pathophysiology.