Renin-Expressing Cells Require ß1-Integrin for Survival and for Development and Maintenance of the Renal Vasculature.

Juxtaglomerular cells are crucial for blood pressure and fluid-electrolyte homeostasis. The factors that maintain the life of renin cells are unknown. In vivo, renin cells receive constant cell-to-cell, mechanical, and neurohumoral stimulation that maintain their identity and function. Whether the presence of this niche is crucial for the vitality of the juxtaglomerular cells is unknown. Integrins are the largest family of cell adhesion molecules that mediate cell-to-cell and cell-to-matrix interactions. Of those, ß1-integrin is the most abundant in juxtaglomerular cells. However, its role in renin cell identity and function has not been ascertained. To test the hypothesis that cell-matrix interactions are fundamental not only to maintain the identity and function of juxtaglomerular cells but also to keep them alive, we deleted ß1-integrin in vivo in cells of the renin lineage. In mutant mice, renin cells died by apoptosis, resulting in decreased circulating renin, hypotension, severe renal-vascular abnormalities, and renal failure. Results indicate that cell-to-cell and cell-to-matrix interactions via ß1-integrin is essential for juxtaglomerular cells survival, suggesting that the juxtaglomerular niche is crucial not only for the tight regulation of renin release but also for juxtaglomerular cell survival-a sine qua non condition to maintain homeostasis.

Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11beta-hydroxysteroid dehydrogenase type 2 in a sex-specific manner.

Intrauterine growth restriction (IUGR) increases the risk of serious adult morbidities such as hypertension. In an IUGR rat model of hypertension, we reported a persistent decrease in kidney 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) mRNA and protein levels from birth through postnatal (P) day 21. This enzyme deficiency can lead to hypertension by limiting renal glucocorticoid deactivation. In the present study, we hypothesized that IUGR affects renal 11beta-HSD2 epigenetic determinants of chromatin structure and alters key transcription factor binding to the 11beta-HSD2 promoter in association with persistent downregulation of its mRNA expression. To test this hypothesis, we performed bilateral uterine artery ligation on embryonic day 19.5 pregnant rats and harvested kidneys at day 0 (P0) and P21. Key transcription factors that can affect 11beta-HSD2 expression include transcriptional enhancers specificity protein 1 (SP1) and NF-kappaB p65 and transcriptional repressors early growth response factor (Egr-1) and NF-kappaB p50. Our most important findings were as follows: 1) IUGR significantly decreased SP1 and NF-kappaB (p65) binding to the 11beta-HSD2 promoter in males, while it increased Egr-1 binding in females and NF-kappaB (p50) binding in males; 2) IUGR increased CpG methylation status, as well as modified the pattern of methylation in several CpG sites of 11beta-HSD2 promoter at P0 also in a sex-specific manner; and 3) IUGR decreased trimethylation of H3K36 in exon 5 of 11beta-HSD2 at P0 and P21 in both genders. We conclude that IUGR is associated with altered transcriptional repressor/activator binding in connection with increased methylation in the 11beta-HSD2 promoter region in a sex-specific manner, possibly leading to decreased transcriptional activity. Furthermore, IUGR decreased trimethylation of H3K36 of the 11beta-HSD2 gene in both genders, which is associated with decreased transcriptional elongation. We speculate that alterations in transcription factor binding and chromatin structure play a role in in utero reprogramming.

Can dysfunctional HDL explain high coronary artery disease risk in South Asians?

BACKGROUND: Coronary artery disease (CAD) is the leading cause of mortality and morbidity in United States, and South Asian immigrants (SAIs) have a higher risk for CAD compare to Caucasians. Traditional risk factors do not completely explain high risk, and some of the unknown risk factors need to be explored. We assessed dysfunctional pro-inflammatory high density lipoprotein (HDL) in SAIs and assessed its association with sub-clinical CAD using carotid intima-media thickness (IMT) as a surrogate marker for atherosclerosis. METHODS: Cross-sectional study on SAIs aged 40-65 years. Sub-clinical CAD was measured using carotid intima media thickness (IMT) as a surrogate marker of atherosclerosis. Dysfunctional or pro-inflammatory HDL was determined by novel cell free assay and HDL inflammatory Index. RESULTS: Dysfunctional HDL was found in the 50% participants, with HDL-inflammatory index of >or=1.00, suggesting pro-inflammatory HDL (95% CI, 0.8772-1.4333). The prevalence of sub-clinical CAD using carotid IMT (>or=0.80 mm) was seen in 41.4% (95% CI, 0.2347-0.5933). On logistic regression analysis, positive carotid IMT was found to be associated with dysfunctional HDL after adjusting for age, family history of cardiovascular disease, and hypertension (p=0.030). CONCLUSIONS: The measurement of HDL level as well as functionality plays an important role in CAD risk assessment. Those SAIs with dysfunctional HDL and without known CAD can be a high risk group requiring treatment with lipid lowering drugs to reduce future risk of CAD. Further large studies are required to explore association of dysfunctional HDL with CAD and identify additional CAD risk caused by dysfunctional HDL.