P2Y<sub>2</sub>receptor activation decreases blood pressure and increases renal Na<sup>+</sup>excretion

Rieg, Timo; Gerasimova, Maria; Boyer, José L.; Insel, Paul A.; Vallon, Volker

doi:10.1152/ajpregu.00148.2011

Cited by 41 publications

(69 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mice were anesthetized with thiobutabarbital (100 mg/kg ip, 2 l/g body wt; Sigma-Aldrich, St. Louis, MO) and ketamine (100 mg/kg im, 2 l/g body wt; Butler, Dublin, OH) and prepared for renal clearance experiments, as described elsewhere (31,32). The jugular vein was cannulated for continuous infusion of 2.25% bovine serum albumin in 0.85% NaCl at 0.4 ml·h Ϫ1 ·30 g body wt Ϫ1 .…”

Section: Methodsmentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

Self Cite

129

111

View full text Add to dashboard Cite

Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na ϩ reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na ϩ excretion, and renal membrane expression of the Na ϩ /H ϩ exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na ϩ reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.glucagon-like peptide-1; dipeptidyl peptidase-4; NHE3; cAMP; proximal tubule GLUCAGON-LIKE PEPTIDE -1 (GLP-1), an incretin hormone secreted from enteroendocrine L cells in the intestine, stimulates glucose-dependent insulin release and may promote preservation of beta-cell function in patients with type 2 diabetes (9, 10). As a consequence, GLP-1 has been a principal focus of clinical and basic diabetes research in recent years. After secretion, active GLP-1 is rapidly cleaved by the widely expressed enzyme dipeptidyl peptidase-4 (DPP-4, CD26), such that the half-life of bioactive GLP-1 is Ͻ3 min. Therefore, therapeutic manipulation of the GLP-1 system includes strategies that inhibit the degradation of GLP-1 by DPP-4 (i.e., DPP-4 inhibitors) or degradation-resistant GLP-1 receptor (GLP-1R) agonists with a longer half-life, such as exendin-4 (EX4) or liraglutide.In addition to its metabolic effects, GLP-1 affects kidney function. Analysis of GLP-1R expression in rats (6), pigs, and humans (34) localized the GLP-1R to the brush border microvilli of proximal tubules. Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6, 30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in...

show abstract

Section: Methodsmentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

Self Cite

129

111

View full text Add to dashboard Cite

show abstract

“…Mice were anesthetized for terminal clearance experiments with 100 mg/kg thiobutabarbital ip and 100 mg/kg ketamine im (30,42). The femoral artery was cannulated for blood sample withdrawal and the jugular vein for continuous maintenance infusion of 2.25 g/dl bovine serum albumin in 0.85% NaCl at a rate of 0.5 ml·h Ϫ1 ·30 g Ϫ1 body wt.…”

Section: Methodsmentioning

confidence: 99%

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Vallon

Eraly

Rao

et al. 2012

American Journal of Physiology-Renal Physiology

Self Cite

104

View full text Add to dashboard Cite

Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 ( Oat1−/−) and OAT3 ( Oat3−/−). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1−/− (−0.03 ± 0.10 μg/min; −3 ± 18%) and Oat3−/− (0.01 ± 0.06 μg/min; −6 ± 19%), with greater variability in Oat1−/−. Expression of OAT3 protein in the renal membranes of Oat1−/− mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3−/− mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3−/− were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.

show abstract

“…56,57 A catheter was placed in the femoral Figure 7. Clearance experiments show higher fractional phosphate excretion and confirm the phosphate wasting phenotype of AC6 artery for continuous BP recording.…”

Section: Effect Of Pth On Urinary P I and Camp Excretion In Renal Clementioning

confidence: 99%

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

Fenton

Murray

Rieg

et al. 2014

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) enhance phosphate excretion by the proximal tubule of the kidney by retrieval of the sodium-dependent phosphate transporters (Npt2a and Npt2c) from the apical plasma membrane. PTH activates adenylyl cyclase (AC) through PTH 1 receptors and stimulates the cAMP/PKA signaling pathway. However, the precise role and isoform(s) of AC in phosphate homeostasis are not known. We report here that mice lacking AC6 (AC6 2/2 ) have increased plasma PTH and FGF-23 levels compared with wild-type (WT) mice but comparable plasma phosphate concentrations. Acute activation of the calcium-sensing receptor or feeding a zero phosphate diet almost completely suppressed plasma PTH levels in both AC6 2/2 and WT mice, indicating a secondary cause for hyperparathyroidism. Pharmacologic blockade of FGF receptors resulted in a comparable increase in plasma phosphate between genotypes, whereas urinary phosphate remained significantly higher in AC6 2/2 mice. Compared with WT mice, AC6 2/2 mice had reduced renal Npt2a and Npt2c protein abundance, with approximately 80% of Npt2a residing in lysosomes. WT mice responded to exogenous PTH with redistribution of Npt2a from proximal tubule microvilli to intracellular compartments and lysosomes alongside a PTH-induced dose-response relationship for fractional phosphate excretion and urinary cAMP excretion. These responses were absent in AC6 2/2 mice. In conclusion, AC6 in the proximal tubule modulates cAMP formation, Npt2a trafficking, and urinary phosphate excretion, which are highlighted by renal phosphate wasting in AC6 2/2 mice. 25: 282225: -283425: , 201425: . doi: 10.1681 Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) are the primary regulators of renal phosphate (P i ) excretion by the proximal tubule and critically involved in the regulation of P i balance and maintenance of plasma P i . PTH acts on the proximal tubule through the G s protein-coupled PTH 1 receptor (PTH 1 R) to stimulate adenylyl cyclase (AC) and, thus, the synthesis of cAMP and consecutive activation of protein kinase A (PKA). 1-3 After activation of PTH 1 R, the sodiumphosphate cotransporters Npt2a and Npt2c (approximately 70% and approximately 30% reabsorption of filtered P i , respectively) are retrieved from the apical plasma membrane, resulting in increased P i excretion. [4][5][6] In addition, cAMP-independent effects of PTH have been reported, 7 which may involve PTH 1 R action on phosphoinositide-specific phospholipase C (PLC) 8,9 and mitogen-activated protein kinases. 10,11 FGF-23 mediates its action in the proximal tubule through the FGF receptor/Klotho complex, which downregulates the expression of Npt2a and Npt2c. 12,13 Immunohistochemistry J Am Soc Nephrol

show abstract

P2Y₂receptor activation decreases blood pressure and increases renal Na⁺excretion

Cited by 41 publications

References 58 publications

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

Contact Info

Product

Resources

About

P2Y2receptor activation decreases blood pressure and increases renal Na+excretion

Cited by 41 publications

References 58 publications

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

Contact Info

Product

Resources

About

P2Y₂receptor activation decreases blood pressure and increases renal Na⁺excretion