Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells

Peti‐Peterdi, Janos; Komlósi, Péter; Fuson, Amanda L.; Guan, Youfei; Schneider, André; Qi, Zhonghua; Redha, Reyadh; Rosivall, László; Breyer, Matthew D.; Bell, P. Darwin

doi:10.1172/jci18018

Cited by 80 publications

(84 citation statements)

References 30 publications

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“…In contrast to the diminished vasoconstricting influence suggested by decreased TxA 2 levels (39) and TxA 2 synthase activity (39) during sodium restriction, the role of PGE 2 via augmented microsomal PGE synthase-1 (20) and prostaglandin (EP 4 ) receptor (19) expression is enhanced. Furthermore, macula densa cells have been shown to release PGE 2 in response to low salt (27). This is consistent with the increased overall COX-2 vasodilatory influence demonstrated Fig.…”

Section: Discussionsupporting

confidence: 82%

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

Green

Rodríguez

Navar

2010

American Journal of Physiology-Renal Physiology

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Green T, Rodriguez J, Navar LG. Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II. Am J Physiol Renal Physiol 299: F954 -F962, 2010. First published July 28, 2010 doi:10.1152/ajprenal.00609.2009.-Nonsteroidal anti-inflammatory drug usage has long revealed renoprotective prostaglandin actions on the renal microvasculature during increased pressor hormone influence, but whether increased cyclooxygenase (COX)-2 expression supports prostaglandin vasodilatory influence by interfering with the actions of ANG II remains unresolved. Therefore, we tested the hypothesis that COX-2 inhibition causes hemodynamic and excretory effects that are increased in proportion to ANG II activity. In anesthetized Sprague-Dawley rats having augmented cortical COX-2 expression but different ANG II activity, we conducted renal clearance experiments during acute inhibition of COX-2 with nimesulide (NMSLD) and inhibition of COX-1 with SC-560. In one series of experiments, acute captopril [acute angiotensin-converting enzyme (ACE) inhibitor (aACEi)] was administered alone (n ϭ 13) or in combination with chronic captopril [chronic ACEi (cACEi)] pretreatment (n ϭ 19). In another series of experiments, rats were fed a normal-sodium [0.4% (NS), n ϭ 12] or a low-sodium [0.03% (LS), n ϭ 18] diet. NMSLD did not alter mean arterial blood pressure in any group but, in the LS and cACEi groups, decreased renal plasma flow (from 3.99 Ϯ 0.33 to 2.85 Ϯ 0.26 and from 4.30 Ϯ 0.19 to 3.22 Ϯ 0.21 ml·min Ϫ1 ·g Ϫ1 ), cortical blood flow (Ϫ12 Ϯ 8% and Ϫ13 Ϯ 4%), and glomerular filtration rate (from 0.88 Ϯ 0.04 to 0.65 Ϯ 0.05 and from 0.95 Ϯ 0.07 to 0.70 Ϯ 0.05 ml·min Ϫ1 ·g Ϫ1 ). In contrast, medullary blood flow (MBF) was significantly decreased by COX-2 inhibition in NS (Ϫ24 Ϯ 5%), LS (Ϫ27 Ϯ 8%), aACEi (Ϫ16 Ϯ 3.8%), and cACEi (Ϫ24 Ϯ 4.2%) groups. Absolute and fractional sodium excretion rates were unchanged by NMSLD, except in the LS group (0.75 Ϯ 0.05 eq/min and 0.43 Ϯ 0.15% and 0.51 Ϯ 0.06 eq/min and 0.26 Ϯ 0.10%). SC-560 did not augment the effects of NMSLD. These results demonstrate an augmented COX-2-mediated vasodilation that is not contingent on ANG II, in contrast to COX-2-mediated augmented sodium excretion, where ANG II activity is requisite. Furthermore, the COX-2 effects on MBF are not contingent on ANG II or changes in cortical microvascular responses. These results reflect COX-2 continual regulation of MBF and adaptive opposition to ANG II prohypertensinogenic effects on renal plasma flow, cortical blood flow, glomerular filtration rate, and absolute and fractional sodium excretion.angiotensin-converting enzyme inhibition; sodium restriction; medullary blood flow THE DYNAMIC PROSTAGLANDIN biosynthetic capacity in the kidney relies on the catalysis of the rate-limiting step by the cyclooxygenase (COX) isoforms COX-1 and COX-2 (25). Adaptive renal responses to reduced sodium intake involve augmented COX activity, along with activation of the renin-angiotensin system (RAS) (21,36,38,41). Interactions of th...

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Section: Discussionsupporting

confidence: 82%

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

Green

Rodríguez

Navar

2010

American Journal of Physiology-Renal Physiology

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“…COX-2 expression increases in the MD in response to a salt-deficient diet and decreases in response to a high-salt diet (13,37). MD sensing of luminal chloride concentration is dependent on net apical transport, mediated by the luminal Na found to be associated with increased COX-2-dependent basolateral PGE 2 release from the MD, further suggesting that COX-2-derived metabolites exert paracrine effects on renin release and arteriolar tone in the neighboring juxtaglomerular apparatus (66). Measurements in vivo in isolated perfused rat kidney and in isolated perfused juxtaglomerular (JG) preparations all indicated that administration of nonspecific COX inhibitors prevents the increases in renin release that are mediated by MD sensing of decreases in luminal NaCl (reviewed in [67,68]).…”

Section: Effects Of Cox-2 Inhibitors On Renin and Renal Hemodynamicsmentioning

confidence: 92%

Update on Cyclooxygenase-2 Inhibitors

Harris

Breyer

2006

Clinical Journal of the American Society of Nephrology

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Nonsteroidal anti-inflammatory drugs represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described side effects can limit their use. Cyclooxygenase-2 (COX-2) inhibitors were initially touted as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of nonspecific nonsteroidal anti-inflammatory drugs. However, in the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. This review summarizes the current state of knowledge about both renal and cardiovascular side effects that are attributed to COX-2 selective inhibitors.Clin J Am Soc Nephrol 1: 236 -245, 2006236 -245, . doi: 10.2215 N onsteroidal anti-inflammatory drugs (NSAID) are the most commonly used class of medications for the treatment of pain and inflammation and represent one of the most common classes of medications used worldwide, with an estimated usage of Ͼ30 million per day (1). Nonselective NSAID inhibit both constitutive cyclooxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2), the rate-limiting enzymes that are involved in production of prostaglandins and thromboxane. In addition to their role in inflammation, prostaglandins are important regulators of vascular tone, salt and water balance, and renin release, and nonselective NSAID exhibit adverse effects, including salt retention and reduced GFR, which may elevate BP or make pre-existing hypertension worse (2). It has been estimated that as many as 2.5 million Americans experience NSAID-mediated renal effects yearly (3). Risk factors that predispose to NSAID-induced renal functional alterations include age Ͼ65 yr, cardiovascular disease, diabetes, male gender, high NSAID dosage, and concurrent use of other nephrotoxic drugs (3). Up to 20% of patients who take nonselective NSAID and have more than one of these risk factors may manifest alterations in renal function.In addition to renal side effects, nonselective NSAID have long been known to predispose to gastrointestinal (GI) toxicity. It has been estimated that one third of patients who taking long-term nonselective NSAID develop endoscopically proven gastric or duodenal ulcers (4). The risk for serious bleeding from these lesions is somewhat lower, with approximately 100,000 hospitalizations for GI complications of NSAID (5). One study estimated that nonselective NSAID-induced GI abnormalities constitute the 15th leading cause of death in the United States (6). The premise that COX-1 performs cellular "housekeeping" functions for normal physiologic activity and is the predominant isoform expressed in platelets and the GI tract, whereas COX-2 acts at inflammatory sites, led to the development of COX-2 selective inhibitors. It also was originally hypothesized that the renal effects of nonselective NSAID were also linked to COX-...

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“…Could the expression of these two pathways in the juxtaglomerular apparatus (JGA) also reflect the existence of vasodepressor mechanisms that might attenuate afferent arteriolar myogenic reactivity in settings in which distal delivery is impaired? Several investigators have demonstrated that signals reflecting reduced distal delivery, such as reduced osmolality or chloride concentration, trigger the release of NO and PGE 2 from the JGA (121,156,170,173), and direct, microelectrode measurements demonstrate an elevation in distal tubular NO concentration in response to furosemide (95). If severe reductions in distal delivery trigger the combined release of NO and PGE 2 , this would be a powerful vasodilator signal.…”

Section: Interactions Between Myogenic and Tgf Mechanismsmentioning

confidence: 99%

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

Loutzenhiser

Griffin²,

Bidani³

2006

American Journal of Physiology-Regulatory, Integrative and Comp

238

244

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dani. Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms. Am J Physiol Regul Integr Comp Physiol 290: R1153-R1167, 2006. doi:10.1152/ajpregu.00402.2005.-When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature. renal microcirculation; afferent arteriole; myogenic; tubuloglomerular feedback ONE OF THE MOST STRIKING CHARACTERISTICS of the renal circulation is the ability of the kidney to maintain a constant renal blood flow (RBF) and glomerular filtration rate (GFR) as renal perfusion pressure is altered. The dual regulation of both RBF and GFR is achieved by proportionate changes in the preglomerular resistance and is believed to be mediated by two mechanisms, tubuloglomerular feedback (TGF) and the renal myogenic response. TGF involves a flow-dependent signal that is sensed at the macula densa and alters tone in the adjacent segment of the afferent arteriole via a mechanism that remains controversial but likely involves adenosine and/or ATP (30,80,144). The myo...

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Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells

Cited by 80 publications

References 30 publications

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

Update on Cyclooxygenase-2 Inhibitors

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

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