Estrogen Receptor α Is Required for Maintaining Baseline Renin Expression

Abstract

Enzymatic cleavage of angiotensinogen by renin represents the critical rate-limiting step in the production of angiotensin-II, but the mechanisms regulating the initial expression of the renin gene remain incomplete. The purpose of this study is to unravel the molecular mechanism controlling renin expression. We identified a subset of nuclear receptors that exhibited an expression pattern similar to renin by reanalyzing a publicly available microarray dataset. Expression of some of these nuclear receptors was similarly regulated as renin in response to physiological cues, which are known to regulate renin. Among these, only estrogen receptor α (ERα) and hepatic nuclear factor α (HNFα) have no known function in regulating renin expression. We determined that ERα is essential for the maintenance of renin expression by transfection of siRNAs targeting Esr1, the gene encoding ERα, in renin-expressing As4.1 cells. We also observed that previously characterized negative regulators of renin expression, Nr2f2 and VDR, exhibited elevated expression in response to ERα inhibition. Therefore, we tested if ERα regulates renin expression through an interaction with Nr2f2 and VDR. Renin expression did not return to baseline when we concurrently suppressed both Esr1 and Nr2f2 or Esr1 and VDR mRNAs, strongly suggesting that Esr1 regulates renin expression independent of Nr2f2 and VDR. ERα directly binds to the hormone response element (HRE) within the renin enhancer region. We conclude that ERα is a previously unknown regulator of renin that directly binds to the renin enhancer HRE sequence and is critical in maintaining renin expression in renin-expressing As4.1 cells.

Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis

“…[62][63][64][65][66] RAAS activity fluctuates with menstrual cycle-showing more activity during the high estrogen luteal phase 67 -and signaling through the alpha estrogen-receptor binds renin enhancer elements necessary for renin expression. 68 In our murine model, it is unclear how sex modifies Panx1-mediated renin suppression. Clearly how estrogen affects RAAS warrants future attention.…”

Macrophage secretion of miR-106b-5p causes renin-dependent hypertension

“…The miR-106b-5p-mediated downregulation of PDE3B and the associated increase in adenylate cyclases, cAMP, and CREB abundance suggest that cAMP signaling is an important contributor to miR-106b-5p-induced renin production 36 . Moreover, deletion of E2f1 26 or Pde3b 27 in mice promotes increased Ppargc1a , Ppars , and Esrra gene expression in tissues requiring a high level of energy for normal physiological function; all these transcription factors are known to increase renin release in JG cells 37 , 38 . These data suggest that miR-106b in JG cells is a global modulator linking cell signaling pathways to transcription factors implicated in renin production and release, and may provide an important target to ameliorate renin-dependent hypertension.…”

RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity

“…Real-time RT-PCR. RNA was extracted from HEK293T cells or aortic tissue, and real-time RT-PCR (qPCR) was performed as previously described (55). Briefly, using oligo (dT) primers, RNaseOUT (Invitrogen, Thermo Fisher Scientific), and SuperScript III (Invitrogen, Thermo Fisher Scientific), cDNA was synthesized from 400 to 700 ng total RNA extracted using RNeasy spin columns (RNeasy Mini Kit, QIAGEN).…”