PGE(2) is a potent stimulator of renin release. So far, the contribution of each of the four PGE(2) receptor subtypes (EP(1)-EP(4)) in the regulation of renin release has not been characterized. Therefore, we investigated the effects PGE(2) on renin secretion rates (RSR) from isolated, perfused kidneys of EP(1)-/-, EP(2)-/-, EP(3)-/-, EP(4)-/-, and wild-type mice. PGE(2) concentration dependently stimulated RSR from kidneys of all four knockout strains with a threshold concentration of 1 nM in EP(1)-/-, EP(2)-/-, EP(3)-/-, and wild-type mice, whereas the threshold concentration was shifted to 10 nM in EP(4)-/- mice. Moreover, the maximum stimulation of RSR by PGE(2) at 1 microM was significantly reduced in EP(4)-/- (12.8-fold of control) and EP(2)-/- (15.9-fold) compared with wild-type (20.7-fold), EP(1)-/- (23.8-fold), and EP(3)-/- (20.1-fold). In contrast, stimulation of RSR by either the loop diuretic bumetanide or the beta-adrenoceptor agonist isoproterenol was similar in all strains. PGE(2) exerted a dual effect on renal vascular tone, inducing vasodilatation at low concentrations (1 nmol/) and vasoconstriction at higher concentrations (100 nmol/) in kidneys of wild-type mice. In kidneys of EP(2)-/- as well as EP(4)-/- mice, vasodilatation at low PGE(2) concentrations was prevented, whereas vasoconstriction at higher concentrations was augmented. In contrast, the vasodilatory component was pronounced in kidneys of EP(1) and EP(3) knockout mice, whereas in both genotypes the vasoconstriction at higher PGE(2) concentrations was markedly blunted. Our data provide evidence that PGE(2) stimulates renin release via activation of EP(2) and EP(4) receptors, whereas EP(1) and EP(3) receptors appear to be without functional relevance in juxtaglomerular cells. In contrast, all four receptor subtypes are involved in the control of renal vascular tone, EP(1) and EP(3) receptors increasing, and EP(2) as well as EP(4) receptors, decreasing it.
Our study suggests that LPEIs with low MWs are promising candidates for non-viral gene delivery, because they are more efficient and substantially less toxic than their higher MW counterparts.
Although the cyclic AMP signalling cascade is considered to be the main activator of renin gene expression in renal juxtaglomerular (JG) cells, the molecular pathways along which cAMP exerts this effect remain a matter of controversy. Here in this study we used the mouse JG cell line As4.1, which shares a number of functional similarities with native JG cells. We found that forskolin, an activator of adenylate cyclase, in the presents of IBMX time-dependently increased renin mRNA levels and prorenin secretion up to threefold. The stimulation of renin gene expression by forskolin/IBMX was markedly attenuated by an inhibitor of protein kinase A (H-89, 10 microM). Forskolin/IBMX had no effect on the decline of renin mRNA after general inhibition of transcription by actinomycin D (2 microM). Conversely, forskolin/IBMX increased the activity of a 2.8-kb fragment of the renin promoter threefold. The promoter region responsible for the stimulatory effect of forskolin/IBMX was narrowed down to three 4 bp of the mouse Ren1(C) gene, which are known as putative CRE-sites. The CRE-binding protein was found to be phosphorylated under forskolin/IBMX stimulation. It appears likely therefore that cAMP stimulates renin gene expression in JG cells by activating protein kinase A and subsequent phosphorylation of the CRE-binding protein.
Tumor necrosis factor-␣ (TNF␣) is known to inhibit renin gene expression in juxtaglomerular cells, which are the main source of renin in vivo. In the present study we aimed to characterize the intracellular mechanisms of TNF␣ signaling to renin gene in the mouse juxtaglomerular cell line As4.1. TNF␣ was found to activate NFB, which is one of the principal intracellular mediators of TNF␣ signal transduction. Constitutive activation of NFB suppressed renin gene transcription, but NFB appeared not to target the NFB binding sites in the renin promoter. Thus, NFB, but not the canonical NFB binding sequences in the renin promoter, seemed to be involved in the suppression of renin transcription by TNF␣. Deletion/mutation analysis revealed that the effect of TNF␣ on renin gene is transmitted by a cAMPresponsive element (CRE) located at ؊2697 to ؊2690. Mobility shift/supershift assays evidenced for the presence of NFB proteins in the complex that binds to mouse renin CRE. Our results strongly suggest that NFB mediates the effect of TNF␣ on renin transcription targeting a CRE in the mouse renin promoter.Renin-angiotensin-aldosterone system (RAAS) 1 is one of the fundamental regulators of blood pressure. Renin, synthesized in the JG cells of the kidney, is the limiting factor that determines the activity of plasma RAAS (1). Therefore renin production is under the strict control of multiple input signals. These could be divided into systematic factors including sodium load, blood pressure, sympathetic tone, plasma concentration of catecholamines and ATII, and local factors including the macula densa signal, nitric oxide, prostaglandins, endothelins, and cytokines (2, 3). Recently (4 -7), the regulatory sequences driving the developmental tissue and cell-specific expression of renin gene have been investigated intensively. However, the intracellular signaling cascades that are utilized by (patho)-physiological extracellular factors to regulate the expression of renin gene are still not well understood. It is established that protein kinase A is involved in the stimulation of renin synthesis. Activated protein kinase A phosphorylates CREB/ATF transcription factors that target a cis-acting CRE to trigger renin transcription. Functional CREs were identified in the promoters of human and mouse renin genes (8 -10). However, there is still relative deficient knowledge about the intracellular signaling and the corresponding cis-regulatory elements, which confer inhibitory signals to renin gene. It is reported that ATII, which is one of the major humoral regulators of renin production, targets the proximal 2.8 kb of the mouse renin promoter to inhibit renin transcription in a protein kinase C-dependent manner (11). The cytokine oncostatin M suppresses renin gene expression by a mechanism involving activation of signal transducers and activators of transcription 5 in As4.1 cells (12). The orphan nuclear receptor Ear2 was identified (13) as a negative regulator of retinoid-induced renin promoter activity also in As4.1 cells. Recentl...
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