Effects of Uroguanylin, an Intestinal Natriuretic Peptide, on Tubuloglomerular Feedback

Wang, Tao; Kurabayashi, Masahiko; Haneda, Manabu; Takabatake, Toshikazu

doi:10.1291/hypres.26.577

Cited by 12 publications

(4 citation statements)

References 27 publications

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“…These findings indicate that UGN inhibits the major route of sodium reabsorption in renal proximal tubules. Our findings also corroborate other studies that suggested the proximal tubule as a target for the UGN natriuretic effect (14,36,49,51).…”

Section: Discussionsupporting

confidence: 92%

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Lessa

Carraro‐Lacroix

Crajoinas

et al. 2012

American Journal of Physiology-Renal Physiology

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-We previously demonstrated that uroguanylin (UGN) significantly inhibits Na ϩ /H ϩ exchanger (NHE)3-mediated bicarbonate reabsorption. In the present study, we aimed to elucidate the molecular mechanisms underlying the action of UGN on NHE3 in rat renal proximal tubules and in a proximal tubule cell line (LLC-PK1). The in vivo studies were performed by the stationary microperfusion technique, in which we measured H ϩ secretion in rat renal proximal segments, through a H ϩ -sensitive microelectrode. UGN (1 M) significantly inhibited the net of proximal bicarbonate reabsorption. The inhibitory effect of UGN was completely abolished by either the protein kinase G (PKG) inhibitor KT5823 or by the protein kinase A (PKA) inhibitor H-89. The effects of UGN in vitro were found to be similar to those obtained by microperfusion. Indeed, we observed that incubation of LLC-PK1 cells with UGN induced an increase in the intracellular levels of cAMP and cGMP, as well as activation of both PKA and PKG. Furthermore, we found that UGN can increase the levels of NHE3 phosphorylation at the PKA consensus sites 552 and 605 in LLC-PK1 cells. Finally, treatment of LLC-PK1 cells with UGN reduced the amount of NHE3 at the cell surface. Overall, our data suggest that the inhibitory effect of UGN on NHE3 transport activity in proximal tubule is mediated by activation of both cGMP/PKG and cAMP/PKA signaling pathways which in turn leads to NHE3 phosphorylation and reduced NHE3 surface expression. Moreover, this study sheds light on mechanisms by which guanylin peptides are intricately involved in the maintenance of salt and water homeostasis. NHE3; uroguanylin; renal microperfusion; bicarbonate reabsorption; cGMP; cAMP IN THE PAST DECADES, IT HAS been postulated that Sta-like guanylin peptides participate in a control system regulating salt balance in response to oral salt intake, linking intestine and kidney in the process of salt and water homeostasis (8,19,22). These peptides are known as endogenous agonists for the Escherichia coli heatstable toxin receptor, guanylate cyclase C (GC-C), uroguanylin (UGN) being its most potent member (12,18,20,27). UGN is a 16 amino acid peptide (27), expressed throughout the intestinal tract, secreted by enterochromaffin cells as prouroguanylin that undergoes postsecretory proteolytic cleavage, generating the active form (15,28,41). Recently, Qian and colleagues (44) demonstrated that the conversion of prouroguanylin to UGN occurs within the lumen of renal tubules.Renal effects of UGN include natriuresis, kaliuresis, diuresis, and increased excretion of cGMP (17,26). In a previous work using stationary in vivo microperfusion, our group demonstrated that UGN perfusion stimulates potassium secretion through Maxi-K channels in connecting and cortical collecting ducts (2). Furthermore, this study demonstrated that UGN perfusion also leads to an inhibition of bicarbonate reabsorption in proximal tubules by reducing the activity of the Na ϩ /H ϩ exchanger, NHE3 isoform (2). In renal proximal tubule cells, NHE...

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Section: Discussionsupporting

confidence: 92%

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Lessa

Carraro‐Lacroix

Crajoinas

et al. 2012

American Journal of Physiology-Renal Physiology

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“…They respond to changes in tubular fluid composition by transmitting signals to the afferent arterioles, thereby regulating the preglomerular vascular resistance and filtered load to the tubules (22). This intriguing mechanism has remained under intensive investigation and the accrued evidence indicates that there are multiple interacting paracrine agents involved in the communication pathway between the macula densa cells and the vascular smooth muscle cells (22,88). Because the TGF mechanism participates in autoregulatory responses of the arteriolar vasculature to changes in renal perfusion pressure, it is also recognized that the mediator of the TGF mechanism contributes to the changes in renal vascular resistance (RVR) associated with autoregulatory responses (21,22).…”

Section: Possible Roles Of Adenosine and Atp In The Tubuloglomerular mentioning

confidence: 99%

Role of Interstitial ATP and Adenosine in the Regulation of Renal Hemodynamics and Microvascular Function

2004

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“…The knockout animals were also found to have increased blood pressure (196). Uroguanylin may complement the renal effects of the cardiac natriuretic peptides, through suppression of the TGF, although its effects on glomerular microcirculation are far less than those of ANP (373).…”

Section: Guanylin and Uroguanylinmentioning

confidence: 99%

Hypertension, Kidney, and Transgenics: A Fresh Perspective

Mullins¹,

Bailey²,

Mullins³

2006

Physiological Reviews

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In this review, we outline the application and contribution of transgenic technology to establishing the genetic basis of blood pressure regulation and its dysfunction. Apart from a small number of examples where high blood pressure is the result of single gene mutation, essential hypertension is the sum of interactions between multiple environmental and genetic factors. Candidate genes can be identified by a variety of means including linkage analysis, quantitative trait locus analysis, association studies, and genome-wide scans. To test the validity of candidate genes, it is valuable to model hypertension in laboratory animals. Animal models generated through selective breeding strategies are often complex, and the underlying mechanism of hypertension is not clear. A complementary strategy has been the use of transgenic technology. Here one gene can be selectively, tissue specifically, or developmentally overexpressed, knocked down, or knocked out. Although resulting phenotypes may still be complicated, the underlying genetic perturbation is a starting point for identifying interactions that lead to hypertension. We recognize that the development and maintenance of hypertension may involve many systems including the vascular, cardiac, and central nervous systems. However, given the central role of the kidney in normal and abnormal blood pressure regulation, we intend to limit our review to models with a broadly renal perspective.

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Effects of Uroguanylin, an Intestinal Natriuretic Peptide, on Tubuloglomerular Feedback

Abstract: Uroguanylin is an endogenous peptide that stimulates cyclic guanosine monophosphate (cGMP) production via the activation of guanylate cyclase C (GC-C) in the intestine and kidney. A high salt diet, but not intra-

Cited by 12 publications

References 27 publications

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Role of Interstitial ATP and Adenosine in the Regulation of Renal Hemodynamics and Microvascular Function

Hypertension, Kidney, and Transgenics: A Fresh Perspective

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