Regulation of Renovascular Adenosine 3′,5′-Cyclic Monophosphate in Spontaneously Hypertensive Rats

Jackson, Edwin K.; Mi, Zaichuan

doi:10.1161/hypertensionaha.109.130542

Cited by 4 publications

(6 citation statements)

References 19 publications

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“…Importantly, the results of the present study are entirely consistent with our previous findings that in isolated, perfused kidneys7 the ability of IBMX and RO 20–1724 to enhance isoproterenol-induced renal venous secretion of 3’,5’-cAMP is greater in kidneys from SHR compared with kidneys from WKY. In addition to providing important confirmation, the present results also extend our previous findings by identifying the vascular smooth muscle cell in the preglomerular microcirculation as the major cell type that contributes to the phenotype of the intact SHR kidney with regard to enhanced responsiveness to broad-spectrum PDE inhibition and PDE4 inhibition specifically.…”

Section: Discussionsupporting

confidence: 92%

“…The results of the present study are also consistent with our previous observation that RO 20–1724 decreases renal vascular resistance in vivo and to a greater extent in SHR than in WKY7. In this regard, an important aspect of the present study is the urinary measurement of 3’,5’-cAMP before and during intravenous infusions of RO 20–1724.…”

Section: Discussionsupporting

confidence: 92%

“…This experiment shows that administration of RO 20–1724 increases urinary 3’,5’-cAMP excretion to a greater extent in SHR than in WKY, a finding consistent with RO 20–1724 increasing renovascular levels of 3’,5’-cAMP more in SHR kidneys. Therefore, this would explain the greater renal hemodynamic response to RO 20–1724 in SHR7. As in the cell culture experiments and as with our previous studies in isolated, pefused kidneys, in the present study the effects of RO 20–1724 are greater in SHR over a dose range.…”

Section: Discussionsupporting

confidence: 84%

“…Because 3’,5’-cAMP regulates renovascular tone1–4 and dysregulation of 3’,5’-cAMP levels in the renal microcirculation may participate in the pathophysiology of genetic hypertension5, 6, we recently examined in isolated, perfused kidneys from genetically hypertensive rats (i.e., spontaneously hypertensive rats; SHR) and normotensive rats (Wistar-Kyoto rats; WKY) the renal venous secretion of 3’,5’-cAMP (a measure of renal vascular 3’,5’-cAMP levels) in response to isoproterenol (β-adrenoceptor agonist)7. The goal of those experiments was to assess the regulation of 3’,5’-cAMP levels in the renal vasculature of SHR versus WKY.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of 3′,5′-cAMP in Preglomerular Smooth Muscle and Endothelial Cells From Genetically Hypertensive Rats

et al. 2010

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Abstract-Our previous studies show that inhibition of phosphodiesterase 4 (PDE4) augments agonist-induced renovascular 3Ј,5Ј-cAMP secretion more in isolated, perfused kidneys from spontaneously hypertensive rats (SHR) versus Wistar-Kyoto normotensive rats (WKY); however, whether this is because of PDE4 inhibition in renovascular smooth muscle cells or endothelial cells is unknown. Therefore, we examined the effects of 3-isobutyl-1-methylxanthine (broad-spectrum PDE inhibitor) and RO 20-1724 (selective PDE4 inhibitor) on isoproterenol-induced 3Ј,5Ј-cAMP levels in cultured WKY and SHR preglomerular vascular smooth muscle and endothelial cells. 3-Isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3Ј,5Ј-cAMP levels similarly in WKY versus SHR endothelial cells. In contrast, 3-isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3Ј,5Ј-cAMP levels significantly more in SHR, compared to WKY, smooth muscle cells (PϽ0.0001). In both cell types from both rat strains, mRNA levels for the PDE4B subtype exceeded levels for the PDE4A, PDE4C, and PDE4D subtypes, and small interfering RNA knockdown of PDE4B mRNA in SHR smooth muscle cells increased isoproterenol-induced 3Ј,5Ј-cAMP. mRNA levels for the PDE4B2 variant exceeded levels for the PDE4B1, PDE4B3, PDE4B4, and PDE4B5 variants. In vivo, infusions of RO 20-1724 increased the urinary excretion of 3Ј,5Ј-cAMP more in SHR than WKY (Pϭ0.0211). We conclude that (1) the greater effect of PDE4 inhibition on renovascular 3Ј,5Ј-cAMP is mediated by inhibition of PDE4 in renovascular smooth muscle cells, not endothelial cells; (2) the major PDE4 subtype in both renovascular smooth muscle and endothelial cells is PDE4B with variant PDE4B2 likely being dominant; and (3) inhibition of PDE4 in vivo increases renal 3Ј,5Ј-cAMP levels more in genetically hypertensive rats. (Hypertension. 2010;56:1096-1101.)Key Words: 3Ј,5Ј-cAMP Ⅲ phosphodiesterase 4 Ⅲ phosphodiesterase 4B Ⅲ phosphodiesterase 4B2 Ⅲ isoproterenol Ⅲ spontaneously hypertensive rats Ⅲ Wistar-Kyoto rats B ecause 3Ј,5Ј-cAMP regulates renovascular tone 1-4 and dysregulation of 3Ј,5Ј-cAMP levels in the renal microcirculation may participate in the pathophysiology of genetic hypertension, 5,6 we recently examined in isolated, perfused kidneys from genetically hypertensive rats (ie, spontaneously hypertensive rats [SHR]) and normotensive rats (WistarKyoto rats [WKY]) the renal venous secretion of 3Ј,5Ј-cAMP (a measure of renal vascular 3Ј,5Ј-cAMP levels) in response to isoproterenol (␤-adrenoceptor agonist). 7 The goal of those experiments was to assess the regulation of 3Ј,5Ј-cAMP levels in the renal vasculature of SHR versus WKY. Because both the production (via adenylyl cyclase) and metabolism (via phosphodiesterase [PDE]) of 3Ј,5Ј-cAMP influence levels of 3Ј,5Ј-cAMP in the kidney vasculature, we examined renal venous 3Ј,5Ј-cAMP secretion in response to isoproterenol in both the absence and presence of PDE inhibitors. Importantly, renal venous 3Ј,5Ј-cAMP secretion in response to isoprotereno...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Regulation of 3′,5′-cAMP in Preglomerular Smooth Muscle and Endothelial Cells From Genetically Hypertensive Rats

et al. 2010

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“…The purines were administered in random order. The base-line renal perfusion pressure was 47 Ϯ 3 mm Hg, which is normal for the isolated, perfused rat kidney at physiological flow rates because the isolated kidney is maximally vasodilated in the absence of endogenous vasoconstrictors and renal sympathetic tone (39). None of the treatments affected renal perfusion pressure.…”

Section: Metabolism Of Exogenous 3ј5ј-camp 2ј3ј-camp 5ј-amp 3ј-amentioning

confidence: 92%

Extracellular 2′,3′-cAMP Is a Source of Adenosine

Jackson

Ren

2009

Journal of Biological Chemistry

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We discovered that renal injury releases 2,3-cAMP (positional isomer of 3,5-cAMP) into the interstitium. This finding motivated a novel hypothesis: renal injury leads to activation of an extracellular 2,3-cAMP-adenosine pathway (i.e. metabolism of extracellular 2,3-cAMP to 3-AMP and 2-AMP, which are metabolized to adenosine, a retaliatory metabolite). In isolated rat kidneys, arterial infusions of 2,3-cAMP (30 mol/ liter) increased the mean venous secretion of 3-AMP (3,400-fold), 2-AMP (26,000-fold), adenosine (53-fold), and inosine (adenosine metabolite, 30-fold). Renal injury with metabolic inhibitors increased the mean secretion of 2,3-cAMP (29-fold), 3-AMP (16-fold), 2-AMP (10-fold), adenosine (4.2-fold), and inosine (6.1-fold) while slightly increasing 5-AMP (2.4-fold). Arterial infusions of 2-AMP and 3-AMP increased secretion of adenosine and inosine similar to that achieved by 5-AMP. Renal artery infusions of 2,3-cAMP in vivo increased urinary excretion of 2-AMP, 3-AMP and adenosine, and infusions of 2-AMP and 3-AMP increased urinary excretion of adenosine as efficiently as 5-AMP. The implications are that 1) in intact organs, 2-AMP and 3-AMP are converted to adenosine as efficiently as 5-AMP (previously considered the most important adenosine precursor) and 2) because 2,3-cAMP opens mitochondrial permeability transition pores, a pro-apoptotic/pronecrotic process, conversion of 2,3-cAMP to adenosine by the extracellular 2,3-cAMP-adenosine pathway would protect tissues by reducing a pro-death factor (2,3-cAMP) while increasing a retaliatory metabolite (adenosine).Our past work supports the existence of a biochemical mechanism of adenosine biosynthesis that involves 3Ј,5Ј-cAMP and that contributes to the extracellular levels of adenosine, i.e. the extracellular 3Ј,5Ј-cAMP-adenosine pathway (Fig. 1, left side) (1-20). In this regard, we propose that the extracellular 3Ј,5Ј-cAMP-adenosine pathway involves four sequential steps that are spatially linked and occur on a quasi-solid surface (i.e. the membrane surface). The four sequential steps are: 1) receptormediated intracellular production of 3Ј,5Ј-cAMP; 2) active transport of 3Ј,5Ј-cAMP from the intracellular compartment to the cell surface; 3) extracellular metabolism of 3Ј,5Ј-cAMP to 5Ј-AMP; and 4) extracellular conversion of 5Ј-AMP to adenosine. Independent laboratories now confirm the existence of the extracellular 3Ј,5Ј-cAMP-adenosine pathway in pial microvessels (21) and more recently in skeletal muscle (22) and the gastrointestinal tract (23). Moreover, Müller et al. (24) report the existence of a 3Ј,5Ј-cAMP-adenosine pathway in which the sequential conversion of 3Ј,5Ј-cAMP to 5Ј-AMP and 5Ј-AMP to adenosine occurs on the outward facing membrane surface of lipid droplets within adipocytes.To study in more detail the role of 3Ј,5Ј-cAMP-adenosine pathway in the kidney, we recently developed a novel assay to measure 3Ј,5Ј-cAMP and other purines in the renal venous effluent from isolated, perfused kidneys (25). Unlike commercially available kits for 3Ј,5...

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Role of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in the renal 2′,3′-cAMP-adenosine pathway

Jackson

Gillespie

et al. 2014

American Journal of Physiology-Renal Physiology

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Energy depletion increases the renal production of 2=,3=-cAMP (a positional isomer of 3=,5=-cAMP that opens mitochondrial permeability transition pores) and 2=,3=-cAMP is converted to 2=-AMP and 3=-AMP, which in turn are metabolized to adenosine. Because the enzymes involved in this "2=,3=-cAMP-adenosine pathway" are unknown, we examined whether 2=,3=-cyclic nucleotide 3=-phosphodiesterase (CNPase) participates in the renal metabolism of 2=,3=-cAMP. Western blotting and real-time PCR demonstrated expression of CNPase in rat glomerular mesangial, preglomerular vascular smooth muscle and endothelial, proximal tubular, thick ascending limb and collecting duct cells. Real-time PCR established the expression of CNPase in human glomerular mesangial, proximal tubular and vascular smooth muscle cells; and the level of expression of CNPase was greater than that for phosphodiesterase 4 (major enzyme for the metabolism of 3=,5=-cAMP). Overexpression of CNPase in rat preglomerular vascular smooth muscle cells increased the metabolism of exogenous 2=,3=-cAMP to 2=-AMP. Infusions of 2=,3=-cAMP into isolated CNPase wild-type (ϩ/ϩ) kidneys increased renal venous 2=-AMP, and this response was diminished by 63% in CNPase knockout (Ϫ/Ϫ) kidneys, whereas the conversion of 3=,5=-cAMP to 5=-AMP was similar in CNPase ϩ/ϩ vs. Ϫ/Ϫ kidneys. In CNPase ϩ/ϩ kidneys, energy depletion (metabolic poisons) increased kidney tissue levels of adenosine and its metabolites (inosine, hypoxanthine, xanthine, and uric acid) without accumulation of 2=,3=-cAMP. In contrast, in CNPase Ϫ/Ϫ kidneys, energy depletion increased kidney tissue levels of 2=,3=-cAMP and abolished the increase in adenosine and its metabolites. In conclusion, kidneys express CNPase, and renal CNPase mediates in part the renal 2=,3=-cAMPadenosine pathway.2=,3=-cyclic adenosine monophosphate; 2=-adenosine monophosphate; 3=-adenosine monophosphate; adenosine; 2=,3=-cyclic nucleotide 3=-phosphodiesterase; CNPase IN RESPONSE TO INJURY, RAT (27,45) and mouse (25) kidneys can produce 2=,3=-cAMP, a positional isomer of 3=,5=-cAMP that is generated when mRNA is enzymatically degraded (27). Moreover, kidneys metabolize 2=,3=-cAMP to 2=-AMP and 3=-AMP and convert 2=-AMP and 3=-AMP to adenosine (25,27). This sequence of reactions is called the "2=,3=-cAMP-adenosine pathway" (2=,3=-cAMP ¡ 2=-AMP ϩ 3=-AMP ¡ adenosine).It is conceivable that the 2=,3=-cAMP-adenosine pathway is a determinant of outcomes following acute injury kidney (AKI). In this regard, work by Azarashvili et al. (2) shows that 2=,3=-cAMP opens mitochondrial permeability transition pores (MPTPs), and it is well-established that a high level of opening of MPTPs leads to apoptosis and necrosis (30); MPTP opening may be particularly important in the pathophysiology AKI (6, 7, 37, 52). On the other hand, it is also conceivable that a moderate level of MPTP activation preconditions organ systems and thus protects against tissue injury (47). Studies also suggest that adenosine may protect against AKI. For example, pivotal studies by ...

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Regulation of Renovascular Adenosine 3′,5′-Cyclic Monophosphate in Spontaneously Hypertensive Rats

Cited by 4 publications

References 19 publications

Regulation of 3′,5′-cAMP in Preglomerular Smooth Muscle and Endothelial Cells From Genetically Hypertensive Rats

Regulation of 3′,5′-cAMP in Preglomerular Smooth Muscle and Endothelial Cells From Genetically Hypertensive Rats

Extracellular 2′,3′-cAMP Is a Source of Adenosine

Role of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in the renal 2′,3′-cAMP-adenosine pathway

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