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1
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Thimm C, Adjaye J. Untangling the Uncertain Role of Overactivation of the Renin-Angiotensin-Aldosterone System with the Aging Process Based on Sodium Wasting Human Models. Int J Mol Sci 2024; 25:9332. [PMID: 39273282 PMCID: PMC11394713 DOI: 10.3390/ijms25179332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/20/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.
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Affiliation(s)
- Chantelle Thimm
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
- Zayed Centre for Research into Rare Diseases in Children (ZCR), EGA Institute for Women’s Health, University College London (UCL), 20 Guilford Street, London WC1N 1DZ, UK
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2
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Powell NR, Shugg T, Leighty J, Martin M, Kreutz RP, Eadon MT, Lai D, Lu T, Skaar TC. Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension. Chronic Dis Transl Med 2024; 10:102-117. [PMID: 38872760 PMCID: PMC11166681 DOI: 10.1002/cdt3.103] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/23/2023] [Accepted: 11/06/2023] [Indexed: 06/15/2024] Open
Abstract
Background Hypertension (HTN) involves genetic variability in the renin-angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen (AGT) messenger RNA (mRNA) is endogenously bound by miR-122-5p and rs699 A > G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq. The AGT promoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases AGT transcription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C > T counterbalances AGT decreased by rs699 A > G, and when these variants occur independently, it translates to HTN-related phenotypes. Methods We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis. Results In silico, rs699 A > G is predicted to increase miR-122-5p binding affinity by 3%. Mir-eCLIP results show rs699 is 40-45 nucleotides from the strongest microRNA-binding site in the AGT mRNA. Unexpectedly, rs699 A > G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression model. Genotype-Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A > G occurs independently from rs5051 C > T. However, GTEx and the in vitro experiments suggest rs699 A > G confers cell-type-specific effects on AGT mRNA abundance, and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A > G associations with HTN. Conclusions We found that rs5051 C > T and rs699 A > G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a fourfold larger effect than in White participants. Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C > T or rs699 A > G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.
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Affiliation(s)
- Nicholas R. Powell
- Division of Clinical Pharmacology, Department of MedicineSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
| | - Tyler Shugg
- Division of Clinical Pharmacology, Department of MedicineSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
| | - Jacob Leighty
- Division of Clinical Pharmacology, Department of MedicineSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
| | - Matthew Martin
- Department of Pharmacology and ToxicologySchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
| | - Rolf P. Kreutz
- Department of CardiologySchool of Medicine, Krannert Institute of Cardiology, Indiana UniversityIndianapolisIndianaUSA
| | - Michael T. Eadon
- Division of Nephrology, Department of MedicineSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
- Department of Medical and Molecular GeneticsSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
| | - Dongbing Lai
- Department of Medical and Molecular GeneticsSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
| | - Tao Lu
- Department of Pharmacology and ToxicologySchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
| | - Todd C. Skaar
- Division of Clinical Pharmacology, Department of MedicineSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
- Department of Medical and Molecular GeneticsSchool of Medicine, Indiana UniversityIndianapolisIndianaUSA
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3
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Li X, Zhuo J. Intracellular Angiotensin II Stimulation of Sodium Transporter Expression in Proximal Tubule Cells via AT 1 (AT 1a) Receptor-Mediated, MAP Kinases ERK1/2- and NF-кB-Dependent Signaling Pathways. Cells 2023; 12:1492. [PMID: 37296613 PMCID: PMC10252550 DOI: 10.3390/cells12111492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
The current prevailing paradigm in the renin-angiotensin system dictates that most, if not all, biological, physiological, and pathological responses to its most potent peptide, angiotensin II (Ang II), are mediated by extracellular Ang II activating its cell surface receptors. Whether intracellular (or intracrine) Ang II and its receptors are involved remains incompletely understood. The present study tested the hypothesis that extracellular Ang II is taken up by the proximal tubules of the kidney by an AT1 (AT1a) receptor-dependent mechanism and that overexpression of an intracellular Ang II fusion protein (ECFP/Ang II) in mouse proximal tubule cells (mPTC) stimulates the expression of Na+/H+ exchanger 3 (NHE3), Na+/HCO3- cotransporter, and sodium and glucose cotransporter 2 (Sglt2) by AT1a/MAPK/ERK1/2/NF-kB signaling pathways. mPCT cells derived from male wild-type and type 1a Ang II receptor-deficient mice (Agtr1a-/-) were transfected with an intracellular enhanced cyan fluorescent protein-tagged Ang II fusion protein, ECFP/Ang II, and treated without or with AT1 receptor blocker losartan, AT2 receptor blocker PD123319, MEK1/MEK2 inhibitor U0126, NF-кB inhibitor RO 106-9920, or p38 MAP kinase inhibitor SB202196, respectively. In wild-type mPCT cells, the expression of ECFP/Ang II significantly increased NHE3, Na+/HCO3-, and Sglt2 expression (p < 0.01). These responses were accompanied by >3-fold increases in the expression of phospho-ERK1/2 and the p65 subunit of NF-кB (p < 0.01). Losartan, U0126, or RO 106-9920 all significantly attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). Deletion of AT1 (AT1a) receptors in mPCT cells attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). Interestingly, the AT2 receptor blocker PD123319 also attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). These results suggest that, similar to extracellular Ang II, intracellular Ang II may also play an important role in Ang II receptor-mediated proximal tubule NHE3, Na+/HCO3-, and Sglt2 expression by activation of AT1a/MAPK/ERK1/2/NF-kB signaling pathways.
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Affiliation(s)
- Xiaochun Li
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA;
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA
| | - Jialong Zhuo
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA;
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA
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4
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Smith D, Layton A. The intrarenal renin-angiotensin system in hypertension: insights from mathematical modelling. J Math Biol 2023; 86:58. [PMID: 36952058 DOI: 10.1007/s00285-023-01891-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/14/2023] [Accepted: 02/21/2023] [Indexed: 03/24/2023]
Abstract
The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II-induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can be removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1R-mediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS.
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Affiliation(s)
- Delaney Smith
- Department of Applied Mathematics, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada.
| | - Anita Layton
- Department of Applied Mathematics, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
- Cheriton School of Computer Science, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
- Department of Biology, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
- School of Pharmacy, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
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5
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Panova AS. Development of concepts on sodium regulation in XX century. RUDN JOURNAL OF MEDICINE 2022. [DOI: 10.22363/2313-0245-2022-26-2-203-212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
The 20th century is the time of the birth of many scientific areas, including the physiology of the kidneys and water-salt metabolism. This article is devoted to the history of the development of one of its directions - the issue of regulation of sodium homeostasis in the body. This article is the first attempt in the Russianspeaking space to summarize the achievements in the study of sodium regulation. For many decades, scientists from different countries have studied the influence of various factors on sodium excretion: blood pressure, atrial peptides, hormones of the neurohypophysis and adrenal glands, renal nerves, infusion of various substances, etc. It was found that sodium excretion does not directly depend on changes in blood pressure and glomerular filtration rate. Atrial peptides causing natriuresis were discovered, their structure and mechanism of action were described in detail. The role of the hormones of the neurohypophysis - vasopressin and oxytocin - in the excretion of sodium, as well as the role of aldosterone and angiotensin II in the reabsorption of this cation was shown. It has been shown that the administration of hypertonic solutions of sodium chloride causes a greater natriuretic response than the administration of other substances (sodium sulfate and acetate, glucose, mannitol, etc.), and the idea of the existence of sodium-s ensitive receptors has also been put forward.
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6
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Hanna FS, Alkhouri S, Rajagopalan C, Ji K, Mattingly RR, Yingst DR. Ang II acutely stimulates Na,K-pump in cells from proximal tubules by increasing its phosphorylation at S938 via a PI3K/AKT pathway. Physiol Rep 2022; 10:e15508. [PMID: 36377055 PMCID: PMC9663852 DOI: 10.14814/phy2.15508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/10/2022] [Accepted: 10/14/2022] [Indexed: 06/16/2023] Open
Abstract
Angiotensin II (Ang II)-dependent stimulation of the AT1 receptor in proximal tubules increases sodium reabsorption and blood pressure. Reabsorption is driven by the Na,K-pump that is acutely stimulated by Ang II, which requires phosphorylation of serine-938 (S938). This site is present in humans and only known to phosphorylated by PKA. Yet, activation of AT1 decreases cAMP required to activate PKA and inhibiting PKA does not block Ang II-dependent phosphorylation of S938. We tested the hypothesis that Ang II-dependent activation is mediated via increased phosphorylation at S938 through a PI3K/AKT-dependent pathway. Experiments were conducted using opossum kidney cells, a proximal tubule cell line, stably co-expressing the AT1 receptor and either the wild-type (α-1.wild-type) or an alanine substituted (α-1.S938A) form of rat kidney Na,K-pump. A 5-min exposure to 10 pM Ang II significantly activated Na,K-pump activity (56%) measured as short-circuit current across polarized α-1.wild-type cells. Wortmannin, at a concentration that selectively inhibits PI3K, blocked that Ang II-dependent activation. Ang II did not stimulate Na,K-pump activity in α-1.S938A cells. Ang II at 10 and 100 pM increased phosphorylation at S938 in α-1.wild-type cells measured in whole cell lysates. The increase was inhibited by wortmannin plus H-89, an inhibitor of PKA, not by either alone. Ang II activated AKT inhibited by wortmannin, not H-89. These data support our hypothesis and show that Ang II-dependent phosphorylation at S938 stimulates Na,K-pump activity and transcellular sodium transport.
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Affiliation(s)
- Fadia S. Hanna
- Department of PhysiologyWayne State University, School of MedicineDetroitMichiganUSA
| | - Samaa Alkhouri
- Department of PhysiologyWayne State University, School of MedicineDetroitMichiganUSA
| | - Carthic Rajagopalan
- Department of PhysiologyWayne State University, School of MedicineDetroitMichiganUSA
| | - Kyungmin Ji
- Department of PharmacologyWayne State University, School of MedicineDetroitMichiganUSA
| | - Raymond R. Mattingly
- Present address:
Department of Pharmacology & ToxicologyBrody School of Medicine, East Carolina UniversityGreenvilleNorth CarolinaUSA
| | - Douglas R. Yingst
- Department of PhysiologyWayne State University, School of MedicineDetroitMichiganUSA
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7
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Nwia SM, Li XC, Leite APDO, Hassan R, Zhuo JL. The Na +/H + Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension. Front Physiol 2022; 13:861659. [PMID: 35514347 PMCID: PMC9062697 DOI: 10.3389/fphys.2022.861659] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/25/2022] [Indexed: 01/29/2023] Open
Abstract
The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid-base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.
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Affiliation(s)
- Sarah M. Nwia
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Xiao Chun Li
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Ana Paula de Oliveira Leite
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Rumana Hassan
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jia Long Zhuo
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States,*Correspondence: Jia Long Zhuo,
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8
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Leite APDO, Li XC, Nwia SM, Hassan R, Zhuo JL. Angiotensin II and AT 1a Receptors in the Proximal Tubules of the Kidney: New Roles in Blood Pressure Control and Hypertension. Int J Mol Sci 2022; 23:2402. [PMID: 35269547 PMCID: PMC8910592 DOI: 10.3390/ijms23052402] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/15/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.
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Affiliation(s)
- Ana Paula de Oliveira Leite
- Tulane Hypertension and Renal Center of Excellence, 1430 Tulane Avenue, New Orleans, LA 70112, USA; (A.P.d.O.L.); (X.C.L.); (S.M.N.); (R.H.)
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Xiao C. Li
- Tulane Hypertension and Renal Center of Excellence, 1430 Tulane Avenue, New Orleans, LA 70112, USA; (A.P.d.O.L.); (X.C.L.); (S.M.N.); (R.H.)
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Sarah M. Nwia
- Tulane Hypertension and Renal Center of Excellence, 1430 Tulane Avenue, New Orleans, LA 70112, USA; (A.P.d.O.L.); (X.C.L.); (S.M.N.); (R.H.)
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Rumana Hassan
- Tulane Hypertension and Renal Center of Excellence, 1430 Tulane Avenue, New Orleans, LA 70112, USA; (A.P.d.O.L.); (X.C.L.); (S.M.N.); (R.H.)
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Jia L. Zhuo
- Tulane Hypertension and Renal Center of Excellence, 1430 Tulane Avenue, New Orleans, LA 70112, USA; (A.P.d.O.L.); (X.C.L.); (S.M.N.); (R.H.)
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
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9
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Li XC, Leite APO, Zheng X, Zhao C, Chen X, Zhang L, Zhou X, Rubera I, Tauc M, Zhuo JL. Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II-Induced Hypertension in PT- Agtr1a-/- Mice. Hypertension 2021; 77:1285-1298. [PMID: 33641366 DOI: 10.1161/hypertensionaha.120.16336] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
[Figure: see text].
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Affiliation(s)
- Xiao Chun Li
- From the Tulane Hypertension and Renal Center of Excellence (X.C.L., A.P.O.L., L.Z., J.L.Z.).,Department of Physiology, Tulane University School of Medicine, New Orleans, LA (X.C.L., A.P.O.L., L.Z., J.L.Z.)
| | - Ana Paula Oliveira Leite
- From the Tulane Hypertension and Renal Center of Excellence (X.C.L., A.P.O.L., L.Z., J.L.Z.).,Department of Physiology, Tulane University School of Medicine, New Orleans, LA (X.C.L., A.P.O.L., L.Z., J.L.Z.)
| | - Xiaowen Zheng
- Department of Emergency Medicine, Guangxi Medical University, Nanning, China (X. Zheng, C.Z.)
| | - Chunling Zhao
- Department of Emergency Medicine, Guangxi Medical University, Nanning, China (X. Zheng, C.Z.)
| | - Xu Chen
- Department of Physiology (X.C.), University of Mississippi Medical Center, Jackson
| | - Liang Zhang
- From the Tulane Hypertension and Renal Center of Excellence (X.C.L., A.P.O.L., L.Z., J.L.Z.).,Department of Physiology, Tulane University School of Medicine, New Orleans, LA (X.C.L., A.P.O.L., L.Z., J.L.Z.)
| | - Xinchun Zhou
- Department of Pathology (X. Zhou), University of Mississippi Medical Center, Jackson
| | - Isabelle Rubera
- Université Côte d'Azur, CNRS UMR-7370, Laboratoire de Physiomédecine Moléculaire, Nice, France (I.R., M.T.)
| | - Michel Tauc
- Université Côte d'Azur, CNRS UMR-7370, Laboratoire de Physiomédecine Moléculaire, Nice, France (I.R., M.T.)
| | - Jia Long Zhuo
- From the Tulane Hypertension and Renal Center of Excellence (X.C.L., A.P.O.L., L.Z., J.L.Z.).,Department of Physiology, Tulane University School of Medicine, New Orleans, LA (X.C.L., A.P.O.L., L.Z., J.L.Z.)
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10
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Ávalos Prado P, Häfner S, Comoglio Y, Wdziekonski B, Duranton C, Attali B, Barhanin J, Sandoz G. KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies. Cell 2020; 184:534-544.e11. [PMID: 33373586 DOI: 10.1016/j.cell.2020.11.047] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 10/22/2020] [Accepted: 11/25/2020] [Indexed: 11/27/2022]
Abstract
Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to the voltage-gated ion channel superfamily, associates to its β-auxiliary subunit KCNE1 to generate the slow cardiac potassium IKs current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily. Strikingly, assembly with KCNE1 switches TMEM16A from a calcium-dependent to a voltage-dependent ion channel. Importantly, clinically relevant inherited mutations within the TMEM16A-regulating domain of KCNE1 abolish the TMEM16A modulation, suggesting that the TMEM16A-KCNE1 current may contribute to inherited pathologies. Altogether, these findings challenge the dogma of the specificity of auxiliary subunits regarding protein complexes and questions ion channel classification.
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Affiliation(s)
- Pablo Ávalos Prado
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France
| | - Stephanie Häfner
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France
| | - Yannick Comoglio
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France
| | - Brigitte Wdziekonski
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France
| | - Christophe Duranton
- Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France; Université Côte d'Azur, CNRS, LP2M, Medical Faculty, Nice, France
| | - Bernard Attali
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel
| | - Jacques Barhanin
- Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France; Université Côte d'Azur, CNRS, LP2M, Medical Faculty, Nice, France
| | - Guillaume Sandoz
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France.
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11
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Angiotensin (1-7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor. Cell Signal 2018; 50:9-24. [PMID: 29928987 DOI: 10.1016/j.cellsig.2018.06.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 06/15/2018] [Accepted: 06/16/2018] [Indexed: 12/20/2022]
Abstract
Angiotensin (1-7) has been reported to be a ligand for the GPCR MAS1. Small molecule MAS1 modulators have also been recently characterized. Aside from convincing evidence for MAS1 activation of Gq signaling, little is known about MAS1 mediated signaling pathways initiated by these ligands, especially Ang (1-7). We performed a comprehensive characterization of recombinant MAS1 signaling induced by Ang (1-7) and small molecule ligands through numerous G protein-dependent and independent pathways, and in a signaling pathway agnostic approach. We find that small molecule ligands modulate numerous G protein-dependent and independent pathways through MAS1, including Gq and Gi pathways, GTPγS binding, β-arrestin recruitment, Erk1/2 and Akt phosphorylation, arachidonic acid release, and receptor internalization. Moreover, in dynamic mass redistribution (DMR) assays that provide a pathway-agnostic readout of cellular responses, small molecule agonists produced robust responses. In contrast, Ang (1-7) failed to induce or block signaling in any of these assay platforms. We detected specific binding of radiolabeled Ang (1-7) to rat aortic endothelial cell (RAEC) membranes, but not to recombinant MAS1. Biphasic, concentration-dependent biased signaling responses to Ang II were detected in RAEC. These phases were associated with vastly different DMR characteristics and this likely provides a molecular basis for previously observed concentration-dependent divergent physiological actions of Ang II. Both phases of Ang II signaling in RAECs were potently inhibited by Ang (1-7), providing a plausible molecular mechanism for Ang (1-7) as counter regulator of the Ang II- AT1 axis, responsible at least in part for Ang (1-7) physiological activities.
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12
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Effects of Nitric Oxide on Renal Proximal Tubular Na + Transport. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6871081. [PMID: 29181400 PMCID: PMC5664255 DOI: 10.1155/2017/6871081] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/14/2017] [Indexed: 12/28/2022]
Abstract
Nitric oxide (NO) has a wide variety of physiological functions in the kidney. Besides the regulatory effects in intrarenal haemodynamics and glomerular microcirculation, in vivo studies reported the diuretic and natriuretic effects of NO. However, opposite results showing the stimulatory effect of NO on Na+ reabsorption in the proximal tubule led to an intense debate on its physiological roles. Animal studies have showed the biphasic effect of angiotensin II (Ang II) and the overall inhibitory effect of NO on the activity of proximal tubular Na+ transporters, the apical Na+/H+ exchanger isoform 3, basolateral Na+/K+ ATPase, and the Na+/HCO3− cotransporter. However, whether these effects could be reproduced in humans remained unclear. Notably, our recent functional analysis of isolated proximal tubules demonstrated that Ang II dose-dependently stimulated human proximal tubular Na+ transport through the NO/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway, confirming the human-specific regulation of proximal tubular transport via NO and Ang II. Of particular importance for this newly identified pathway is its possibility of being a human-specific therapeutic target for hypertension. In this review, we focus on NO-mediated regulation of proximal tubular Na+ transport, with emphasis on the interaction with individual Na+ transporters and the crosstalk with Ang II signalling.
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13
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Rigault G, Franko B, Chabre O, Quemerai MA, Nemoz B, Zaoui P. [Hyponatremic-hypertensive syndrome successfully treated by endovascular therapy: A case report]. Ann Cardiol Angeiol (Paris) 2017; 66:243-245. [PMID: 28506580 DOI: 10.1016/j.ancard.2017.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 03/07/2017] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Hyponatremic-hypertensive syndrome (HHS) is characterized by hypertension and hyponatremia. CASE PRESENTATION We report a case of HHS in a 73-year-old woman, revealed by a hyponatremia leading to status epilepticus, without initial hypertension due to hypovolemia. She was successfully treated by endovascular therapy without any long-term supplementation or anti-hypertensive medication. CONCLUSION Physiopathology hypothesis of HHS implicate pressure natriuresis, in this case, hypertension is not initially found and we discuss other hyponatremia mechanisms.
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Affiliation(s)
- G Rigault
- Service de néphrologie, hospital A.-Michallon, boulevard de la Chantourne, 38700 La Tronche, France
| | - B Franko
- Service de néphrologie, hospital A.-Michallon, boulevard de la Chantourne, 38700 La Tronche, France; Service de néphrologie, centre hospitalier Annecy-Genevois, 1, avenue de l'Hôpital, 74370 Metz-Tessy, France.
| | - O Chabre
- Service d'endocrinologie, hospital A.-Michallon, boulevard de la Chantourne, 38700 La Tronche, France
| | - M-A Quemerai
- Service d'endocrinologie, hospital A.-Michallon, boulevard de la Chantourne, 38700 La Tronche, France
| | - B Nemoz
- Département de biologie, institut de biologie et de pathologie, boulevard de la Chantourne, 38700 La Tronche, France
| | - P Zaoui
- Service de néphrologie, hospital A.-Michallon, boulevard de la Chantourne, 38700 La Tronche, France
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14
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Horita S, Nakamura M, Suzuki M, Satoh N, Suzuki A, Homma Y, Nangaku M. The role of renal proximal tubule transport in the regulation of blood pressure. Kidney Res Clin Pract 2017; 36:12-21. [PMID: 28428931 PMCID: PMC5331971 DOI: 10.23876/j.krcp.2017.36.1.12] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 10/18/2016] [Accepted: 12/05/2016] [Indexed: 12/15/2022] Open
Abstract
The electrogenic sodium/bicarbonate cotransporter 1 (NBCe1) on the basolateral side of the renal proximal tubule plays a pivotal role in systemic acid-base homeostasis. Mutations in the gene encoding NBCe1 cause severe proximal renal tubular acidosis accompanied by other extrarenal symptoms. The proximal tubule reabsorbs most of the sodium filtered in the glomerulus, contributing to the regulation of plasma volume and blood pressure. NBCe1 and other sodium transporters in the proximal tubule are regulated by hormones, such as angiotensin II and insulin. Angiotensin II is probably the most important stimulator of sodium reabsorption. Proximal tubule AT1A receptor is crucial for the systemic pressor effect of angiotensin II. In rodents and rabbits, the effect on proximal tubule NBCe1 is biphasic; at low concentration, angiotensin II stimulates NBCe1 via PKC/cAMP/ERK, whereas at high concentration, it inhibits NBCe1 via NO/cGMP/cGKII. In contrast, in human proximal tubule, angiotensin II has a dose-dependent monophasic stimulatory effect via NO/cGMP/ERK. Insulin stimulates the proximal tubule sodium transport, which is IRS2-dependent. We found that in insulin resistance and overt diabetic nephropathy, stimulatory effect of insulin on proximal tubule transport was preserved. Our results suggest that the preserved stimulation of the proximal tubule enhances sodium reabsorption, contributing to the pathogenesis of hypertension with metabolic syndrome. We describe recent findings regarding the role of proximal tubule transport in the regulation of blood pressure, focusing on the effects of angiotensin II and insulin.
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Affiliation(s)
- Shoko Horita
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Motonobu Nakamura
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Masashi Suzuki
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Nobuhiko Satoh
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Atsushi Suzuki
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Yukio Homma
- Department of Urology, The University of Tokyo Hospital, Tokyo, Japan
| | - Masaomi Nangaku
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
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15
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Kang JH, Baik HW, Yoo SM, Kim JH, Cheong HI, Park CG, Kang HG, Ha IS. Aliskiren Regulates Neonatal Fc Receptor and IgG Metabolism with Attenuation of Anti-GBM Glomerulonephritis in Mice. Nephron Clin Pract 2016; 134:272-282. [DOI: 10.1159/000448789] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 07/26/2016] [Indexed: 11/19/2022] Open
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16
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Crajoinas RO, Polidoro JZ, Carneiro de Morais CPA, Castelo-Branco RC, Girardi ACC. Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells. Am J Physiol Cell Physiol 2016; 311:C768-C776. [PMID: 27510906 DOI: 10.1152/ajpcell.00191.2016] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 07/29/2016] [Indexed: 12/16/2022]
Abstract
Binding of angiotensin II (ANG II) to the AT1 receptor (AT1R) in the proximal tubule stimulates Na+/H+ exchanger isoform 3 (NHE3) activity through multiple signaling pathways. However, the effects of ANG II/AT1R-induced inihibitory G protein (Gi) activation and subsequent decrease in cAMP accumulation on NHE3 regulation are not well established. We therefore tested the hypothesis that ANG II reduces cAMP/PKA-mediated phosphorylation of NHE3 on serine 552 and, in doing so, stimulates NHE3 activity. Under basal conditions, ANG II stimulated NHE3 activity but did not affect PKA-mediated NHE3 phosphorylation at serine 552 in opossum kidney (OKP) cells. However, in the presence of the cAMP-elevating agent forskolin (FSK), ANG II blocked FSK-induced NHE3 inhibition, reduced intracellular cAMP concentrations, lowered PKA activity, and prevented the FSK-mediated increase in NHE3 serine 552 phosphorylation. All effects of ANG II were blocked by pretreating OKP cells with the AT1R antagonist losartan, highlighting the contribution of the AT1R/Gi pathway in ANG II-mediated NHE3 upregulation under cAMP-elevating conditions. Accordingly, Gi inhibition by pertussis toxin treatment decreased NHE3 activity both in vitro and in vivo and, more importantly, prevented the stimulatory effect of ANG II on NHE3 activity in rat proximal tubules. Collectively, our results suggest that ANG II counteracts the effects of cAMP/PKA on NHE3 phosphorylation and inhibition by activating the AT1R/Gi pathway. Moreover, these findings support the notion that NHE3 dephosphorylation at serine 552 may represent a key event in the regulation of renal proximal tubule sodium handling by ANG II in the presence of natriuretic hormones that promote cAMP accumulation and transporter phosphorylation.
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Affiliation(s)
- Renato O Crajoinas
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil; and
| | - Juliano Z Polidoro
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil; and
| | - Carla P A Carneiro de Morais
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil; and
| | - Regiane C Castelo-Branco
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, São Paulo, São Paulo, Brazil
| | - Adriana C C Girardi
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil; and
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17
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Hiranyachattada S, Harris PJ. Regulation of renal proximal fluid uptake by luminal and peritubular angiotensin II. J Renin Angiotensin Aldosterone Syst 2016; 5:89-92. [PMID: 15295721 DOI: 10.3317/jraas.2004.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Introduction Angiotensin II (Ang II), when administered to either tubular lumen or peritubular capillary, exerts a biphasic action on proximal fluid uptake rate. At low concentrations, (10-12—10-10M) Ang II stimulates fluid transport, whereas higher doses (> 10-9 M) inhibit. Ang II is secreted into the lumen in the proximal tubule and the concentration of Ang II in the proximal lumen has been reported to be in the nanomolar range, 100—1,000 times higher than in peritubular blood. We investigated the regulation of renal proximal fluid transport by luminal (predominantly locally produced) and peritubular capillary (circulatory) Ang II in anaesthetised rats, using a selective AT1-receptor antagonist, candesartan.
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18
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Hatanaka M, Kaimori JY, Yamamoto S, Matsui I, Hamano T, Takabatake Y, Ecelbarger CM, Takahara S, Isaka Y, Rakugi H. Azilsartan Improves Salt Sensitivity by Modulating the Proximal Tubular Na+-H+ Exchanger-3 in Mice. PLoS One 2016; 11:e0147786. [PMID: 26807585 PMCID: PMC4725961 DOI: 10.1371/journal.pone.0147786] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 01/10/2016] [Indexed: 12/27/2022] Open
Abstract
A potent angiotensin II type-1 receptor blocker, azilsartan, has been reported to reduce blood pressure more effectively than candesartan. Interestingly, azilsartan can also restore the circadian rhythm of blood pressure. We hypothesized that azilsartan could also improve salt sensitivity; thus, we examined the effect of azilsartan on sodium handling in renal tubules. Subtotal nephrectomized C57BL/6 mice received azilsartan (1.0 mg/kg/day), candesartan (0.3 mg/kg/day), or vehicle via the oral route in conjunction with a normal- (0.3%) or high-salt (8.0%) diet. Two weeks later, the azilsartan group showed significantly lower blood pressure during the light period than the candesartan and vehicle groups (azilsartan: 103.1 ± 1.0; candesartan: 111.7 ± 2.7; vehicle: 125.5 ± 2.5 mmHg; P < 0.05; azilsartan or candesartan vs. vehicle). The azilsartan group also showed higher urinary fractional excretion of sodium during the dark period than the candesartan and vehicle groups (azilsartan: 21.37 ± 3.69%; candesartan: 14.17 ± 1.42%; vehicle: 13.85 ± 5.30%; P < 0.05 azilsartan vs. candesartan or vehicle). A pressure—natriuresis curve demonstrated that azilsartan treatment restored salt sensitivity. Immunofluorescence and western blotting showed lower levels of Na+-H+ exchanger-3 (NHE3) protein (the major sodium transporter in renal proximal tubules) in the azilsartan group, but not in the candesartan or vehicle groups. However, azilsartan did not affect NHE3 transcription levels. Interestingly, we did not observe increased expression of downstream sodium transporters, which would have compensated for the increased flow of sodium and water due to non-absorption by NHE3. We also confirmed the mechanism stated above using cultured opossum kidney proximal tubular cells. Results revealed that a proteasomal inhibitor (but not a lysosomal inhibitor) blocked the azilsartan-induced decrease in NHE3 protein expression, suggesting that azilsartan increases NHE3 ubiquitination. In conclusion, azilsartan (but not candesartan) improved salt sensitivity possibly by decreasing NHE3 expression via ubiquitin—proteasomal degradation.
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Affiliation(s)
- Masaki Hatanaka
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Jun-Ya Kaimori
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- * E-mail:
| | - Satoko Yamamoto
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Isao Matsui
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takayuki Hamano
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshitsugu Takabatake
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Carolyn M. Ecelbarger
- Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington D.C., United States of America
| | - Shiro Takahara
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshitaka Isaka
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hiromi Rakugi
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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19
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Boegehold MA, Drenjancevic I, Lombard JH. Salt, Angiotensin II, Superoxide, and Endothelial Function. Compr Physiol 2015; 6:215-54. [PMID: 26756632 DOI: 10.1002/cphy.c150008] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Proper function of the vascular endothelium is essential for cardiovascular health, in large part due to its antiproliferative, antihypertrophic, and anti-inflammatory properties. Crucial to the protective role of the endothelium is the production and liberation of nitric oxide (NO), which not only acts as a potent vasodilator, but also reduces levels of reactive oxygen species, including superoxide anion (O2•-). Superoxide anion is highly injurious to the vasculature because it not only scavenges NO molecules, but has other damaging effects, including direct oxidative disruption of normal signaling mechanisms in the endothelium and vascular smooth muscle cells. The renin-angiotensin system plays a crucial role in the maintenance of normal blood pressure. This function is mediated via the peptide hormone angiotensin II (ANG II), which maintains normal blood volume by regulating Na+ excretion. However, elevation of ANG II above normal levels increases O2•- production, promotes oxidative stress and endothelial dysfunction, and plays a major role in multiple disease conditions. Elevated dietary salt intake also leads to oxidant stress and endothelial dysfunction, but these occur in the face of salt-induced ANG II suppression and reduced levels of circulating ANG II. While the effects of abnormally high levels of ANG II have been extensively studied, far less is known regarding the mechanisms of oxidant stress and endothelial dysfunction occurring in response to chronic exposure to abnormally low levels of ANG II. The current article focuses on the mechanisms and consequences of this less well understood relationship among salt, superoxide, and endothelial function.
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Affiliation(s)
| | - Ines Drenjancevic
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Julian H Lombard
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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20
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Baum M. Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine. Am J Physiol Renal Physiol 2015; 310:F294-9. [PMID: 26661654 DOI: 10.1152/ajprenal.00447.2015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 12/03/2015] [Indexed: 11/22/2022] Open
Abstract
Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100- to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10(-8) M ANG II to the lumen inhibited mTAL chloride transport (220 ± 19 to 165 ± 25 pmol·mm(-1)·min(-1), P < 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10(-6) M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 ± 18 to 364 ± 42 pmol·mm(-1)·min(-1) (P < 0.05). Stimulation of chloride transport by luminal ANG II was also observed with 10(-3) M bath dibutyryl cAMP in the bathing solution and bath isoproterenol. A bath of 10(-5) H-89 blocked the stimulation of chloride transport by norepinephrine and prevented the effect of luminal ANG II to either stimulate or inhibit chloride transport. Bath phentolamine, an α-adrenergic agonist, also prevented the decrease in mTAL chloride transport by luminal ANG II. Thus luminal ANG II increases chloride transport with basolateral norepinephrine; an effect likely mediated by stimulation of cAMP. Alpha-1 adrenergic stimulation prevents the inhibition of chloride transport by luminal ANG II.
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Affiliation(s)
- Michel Baum
- Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
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21
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Javkhedkar AA, Banday AA. Antioxidant resveratrol restores renal sodium transport regulation in SHR. Physiol Rep 2015; 3:3/11/e12618. [PMID: 26603454 PMCID: PMC4673646 DOI: 10.14814/phy2.12618] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 10/16/2015] [Indexed: 01/11/2023] Open
Abstract
Previously we have shown that in spontaneously hypertensive rats (SHR) renal angiotensin (Ang) II receptor (AT1R) upregulation leads to overstimulation of Na/K-ATPase by Ang II. There are reports that antioxidants can reduce oxidative stress and blood pressure (BP) in SHR, however the effect of these compounds on AT1R function remains to be determined. Therefore, we hypothesized that polyphenol antioxidant resveratrol would mitigate oxidative stress, normalize renal AT1R signaling, and reduce BP in SHR. SHR and wistar-kyoto (WKY) rats were treated with resveratrol for 8 weeks. Untreated SHR exhibited oxidative stress and enhanced renal proximal tubular Ang II-induced G-protein activation and Na/K-ATPase stimulation. Treatment of SHR with resveratrol mitigated oxidative stress, reduced BP, and normalized renal AT1R signaling. In SHR, nuclear expression of transcription factor NF-κB was increased while expression of Nrf2 was reduced. SHR also exhibited a significant decrease in renal antioxidant capacity and activities of phase II antioxidant enzymes. Resveratrol treatment of SHR abolished renal NF-κB activation, restored Nrf2-phase II antioxidant signaling and Ang II-mediated Na/K-ATPase regulation. These data show that in SHR, oxidative stress via activation of NF-κB upregulates AT1R–G-protein signaling resulting in overstimulation Na/K-ATPase which contributes to hypertension. Resveratrol, via Nrf2, activates phase II antioxidant enzymes, mitigates oxidative stress, normalizes AT1R–G-protein signaling and Na/K-ATPase regulation, and decreases BP in SHR.
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Affiliation(s)
- Apurva A Javkhedkar
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas
| | - Anees A Banday
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas
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22
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Seki G, Nakamura M, Suzuki M, Satoh N, Horita S. Species differences in regulation of renal proximal tubule transport by certain molecules. World J Nephrol 2015; 4:307-312. [PMID: 25949945 PMCID: PMC4419141 DOI: 10.5527/wjn.v4.i2.307] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 12/24/2014] [Accepted: 01/20/2015] [Indexed: 02/06/2023] Open
Abstract
Renal proximal tubules (PTs) play important roles in the regulation of acid/base, plasma volume and blood pressure. Recent studies suggest that there are substantial species differences in the regulation of PT transport. For example, thiazolidinediones (TZDs) are widely used for the treatment of type 2 diabetes mellitus, but the use of TZDs is associated with fluid overload. In addition to the transcriptional enhancement of sodium transport in distal nephrons, TZDs rapidly stimulate PT sodium transport via a non-genomic mechanism depending on peroxisome proliferator activated receptor γ/Src/epidermal growth factor receptor (EGFR)/MEK/ERK. In mouse PTs, however, TZDs fail to stimulate PT transport probably due to constitutive activation of Src/EGFR/ERK pathway. This unique activation of Src/ERK may also affect the effect of high concentrations of insulin on mouse PT transport. On the other hand, the effect of angiotensin II (Ang II) on PT transport is known to be biphasic in rabbits, rats, and mice. However, Ang II induces a concentration-dependent, monophasic transport stimulation in human PTs. The contrasting responses to nitric oxide/guanosine 3’,5’-cyclic monophosphate pathway may largely explain these different effects of Ang II on PT transport. In this review, we focus on the recent findings on the species differences in the regulation of PT transport, which may help understand the species-specific mechanisms underlying edema formation and/or hypertension occurrence.
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23
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Su Y, Bi J, Pulgar VM, Figueroa J, Chappell M, Rose JC. Antenatal glucocorticoid treatment alters Na+ uptake in renal proximal tubule cells from adult offspring in a sex-specific manner. Am J Physiol Renal Physiol 2015; 308:F1268-75. [PMID: 25834069 DOI: 10.1152/ajprenal.00047.2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/29/2015] [Indexed: 01/01/2023] Open
Abstract
We have shown a sex-specific effect of fetal programming on Na(+) excretion in adult sheep. The site of this effect in the kidney is unknown. Therefore, we tested the hypothesis that renal proximal tubule cells (RPTCs) from adult male sheep exposed to betamethasone (Beta) before birth have greater Na(+) uptake than do RPTCs from vehicle-exposed male sheep and that RPTCs from female sheep similarly exposed are not influenced by antenatal Beta. In isolated RPTCs from 1- to 1.5-yr-old male and female sheep, we measured Na(+) uptake under basal conditions and after stimulation with ANG II. To gain insight into the mechanisms involved, we also measured nitric oxide (NO) levels, ANG II receptor mRNA levels, and expression of Na(+)/H(+) exchanger 3. Basal Na(+) uptake increased more in cells from Beta-exposed male sheep than in cells from vehicle-exposed male sheep (400% vs. 300%, P < 0.00001). ANG II-stimulated Na(+) uptake was also greater in cells from Beta-exposed males. Beta exposure did not increase Na(+) uptake by RPTCs from female sheep. NO production was suppressed more by ANG II in RPTCs from Beta-exposed males than in RPTCs from either vehicle-exposed male or female sheep. Our data suggest that one site of the sex-specific effect of Beta-induced fetal programming in the kidney is the RPTC and that the enhanced Na(+) uptake induced by antenatal Beta in male RPTCs may be related to the suppression of NO in these cells.
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Affiliation(s)
- Yixin Su
- Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Center of Research for Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and
| | - Jianli Bi
- Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Center of Research for Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and
| | - Victor M Pulgar
- Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Center of Research for Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and
| | - Jorge Figueroa
- Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Center of Research for Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and
| | - Mark Chappell
- Hypertension Center, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - James C Rose
- Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Center of Research for Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and
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Ko B, Mistry A, Hanson L, Mallick R, Hoover RS. Mechanisms of angiotensin II stimulation of NCC are time-dependent in mDCT15 cells. Am J Physiol Renal Physiol 2015; 308:F720-7. [PMID: 25651566 DOI: 10.1152/ajprenal.00465.2014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 01/26/2015] [Indexed: 12/17/2022] Open
Abstract
Angiotensin II (ANG II) increases thiazide-sensitive sodium-chloride cotransporter (NCC) activity both acutely and chronically. ANG II has been implicated as a switch that turns WNK4 from an inhibitor of NCC into an activator of NCC, and ANG II's effect on NCC appears to require WNK4. Chronically, ANG II stimulation of NCC results in an increase in total and phosphorylated NCC, but the role of NCC phosphorylation in acute ANG II actions is unclear. Here, using a mammalian cell model with robust native NCC activity, we corroborate the role that ANG II plays in WNK4 regulation and clarify the role of Ste20-related proline alanine-rich kinase (SPAK)-induced NCC phosphorylation in ANG II action. ANG II was noted to have a biphasic effect on NCC, with a peak increase in NCC activity in the physiologic range of 10(-11) M ANG II. This effect was apparent as early as 15 min and remained sustained through 120 min. These changes correlated with significant increases in NCC surface protein expression. Knockdown of WNK4 expression sharply attenuated the effect of ANG II. SPAK knockdown did not affect ANG II action at early time points (15 and 30 min), but it did attenuate the response at 60 min. Correspondingly, NCC phosphorylation did not increase at 15 or 30 min, but increased significantly at 60 min. We therefore conclude that within minutes of an increase in ANG II, NCC is rapidly trafficked to the cell surface in a phosphorylation-independent but WNK4-dependent manner. Then, after 60 min, ANG II induces SPAK-dependent phosphorylation of NCC.
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Affiliation(s)
- Benjamin Ko
- Department of Medicine, University of Chicago, Chicago, Illinois;
| | - Abinash Mistry
- Division of Nephrology, Department of Medicine, Emory University, Atlanta, Georgia; and
| | - Lauren Hanson
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Rickta Mallick
- Division of Nephrology, Department of Medicine, Emory University, Atlanta, Georgia; and
| | - Robert S Hoover
- Division of Nephrology, Department of Medicine, Emory University, Atlanta, Georgia; and Atlanta Veteran's Administration Medical Center, Decatur, Georgia
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25
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Roles of renal proximal tubule transport in acid/base balance and blood pressure regulation. BIOMED RESEARCH INTERNATIONAL 2014; 2014:504808. [PMID: 24982885 PMCID: PMC4058521 DOI: 10.1155/2014/504808] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023]
Abstract
Sodium-coupled bicarbonate absorption from renal proximal tubules (PTs) plays a pivotal role in the maintenance of systemic acid/base balance. Indeed, mutations in the Na+-HCO3− cotransporter NBCe1, which mediates a majority of bicarbonate exit from PTs, cause severe proximal renal tubular acidosis associated with ocular and other extrarenal abnormalities. Sodium transport in PTs also plays an important role in the regulation of blood pressure. For example, PT transport stimulation by insulin may be involved in the pathogenesis of hypertension associated with insulin resistance. Type 1 angiotensin (Ang) II receptors in PT are critical for blood pressure homeostasis. Paradoxically, the effects of Ang II on PT transport are known to be biphasic. Unlike in other species, however, Ang II is recently shown to dose-dependently stimulate human PT transport via nitric oxide/cGMP/ERK pathway, which may represent a novel therapeutic target in human hypertension. In this paper, we will review the physiological and pathophysiological roles of PT transport.
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26
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Shirai A, Yamazaki O, Horita S, Nakamura M, Satoh N, Yamada H, Suzuki M, Kudo A, Kawakami H, Hofmann F, Nishiyama A, Kume H, Enomoto Y, Homma Y, Seki G. Angiotensin II dose-dependently stimulates human renal proximal tubule transport by the nitric oxide/guanosine 3',5'-cyclic monophosphate pathway. J Am Soc Nephrol 2014; 25:1523-32. [PMID: 24511122 DOI: 10.1681/asn.2013060596] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Stimulation of renal proximal tubule (PT) transport by angiotensin II (Ang II) is critical for regulation of BP. Notably, in rats, mice, and rabbits, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II but inhibited by nanomolar to micromolar concentrations of Ang II. However, little is known about the effects of Ang II on human PT transport. By functional analysis with isolated PTs obtained from nephrectomy surgery, we found that Ang II induces a dose-dependent profound stimulation of human PT transport by type 1 Ang II receptor (AT1)-dependent phosphorylation of extracellular signal-regulated kinase (ERK). In PTs of wild-type mice, the nitric oxide (NO) /cGMP/cGMP-dependent kinase II (cGKII) pathway mediated the inhibitory effect of Ang II. In PTs of cGKII-deficient mice, the inhibitory effect of Ang II was lost, but activation of the NO/cGMP pathway failed to phosphorylate ERK. Conversely, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II by phosphorylating ERK independently of cGKII. These contrasting responses to the NO/cGMP pathway may largely explain the different modes of PT transport regulation by Ang II, and the unopposed marked stimulation of PT transport by high intrarenal concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Additionally, the previously unrecognized stimulatory effect of the NO/cGMP pathway on PT transport may represent a human-specific therapeutic target in hypertension.
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Affiliation(s)
| | | | | | | | | | | | | | - Akihiko Kudo
- Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan
| | - Hayato Kawakami
- Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan
| | - Franz Hofmann
- Forschergruppe 923, Institut für Pharmakologie und Toxikologie der Technischen Universität München, München, Germany; and
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Haruki Kume
- Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yutaka Enomoto
- Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yukio Homma
- Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
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Cabral PD, Hong NJ, Hye Khan MA, Ortiz PA, Beierwaltes WH, Imig JD, Garvin JL. Fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. Hypertension 2013; 63:e68-73. [PMID: 24379189 DOI: 10.1161/hypertensionaha.113.02564] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The proximal nephron reabsorbs 60% to 70% of the fluid and sodium and most of the filtered bicarbonate via Na/H exchanger 3. Enhanced proximal nephron transport is implicated in hypertension. Our findings show that a fructose-enriched diet causes salt sensitivity. We hypothesized that fructose stimulates luminal Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. Na/H exchange was measured in rat proximal tubules as the rate of intracellular pH (pHi) recovery in fluorescent units/s. Replacing 5 mmol/L glucose with 5 mmol/L fructose increased the rate of pHi recovery (1.8±0.6 fluorescent units/s; P<0.02; n=8). Staurosporine, a protein kinase C inhibitor, blocked this effect. We studied whether this effect was because of the addition of fructose or removal of glucose. The basal rate of pHi recovery was first tested in the presence of a 0.6-mmol/L glucose and 1, 3, or 5 mmol/L fructose added in a second period. The rate of pHi recovery did not change with 1 mmol/L but it increased with 3 and 5 mmol/L of fructose. Adding 5 mmol/L glucose caused no change. Removal of luminal sodium blocked pHi recovery. With 5.5 mmol/L glucose, angiotensin II (1 pmol/L) did not affect the rate of pHi recovery (change, -1.1±0.5 fluorescent units/s; n=9) but it increased the rate of pHi recovery with 0.6 mmol/L glucose/5 mmol/L fructose (change, 4.0±2.2 fluorescent units/s; P<0.02; n=6). We conclude that fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. This mechanism is likely dependent on protein kinase C. These results may partially explain the mechanism by which a fructose diet induces hypertension.
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Affiliation(s)
- Pablo D Cabral
- Department of Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4970.
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28
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Moss R, Thomas SR. Hormonal regulation of salt and water excretion: a mathematical model of whole kidney function and pressure natriuresis. Am J Physiol Renal Physiol 2013; 306:F224-48. [PMID: 24107423 DOI: 10.1152/ajprenal.00089.2013] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
We present a lumped-nephron model that explicitly represents the main features of the underlying physiology, incorporating the major hormonal regulatory effects on both tubular and vascular function, and that accurately simulates hormonal regulation of renal salt and water excretion. This is the first model to explicitly couple glomerulovascular and medullary dynamics, and it is much more detailed in structure than existing whole organ models and renal portions of multiorgan models. In contrast to previous medullary models, which have only considered the antidiuretic state, our model is able to regulate water and sodium excretion over a variety of experimental conditions in good agreement with data from experimental studies of the rat. Since the properties of the vasculature and epithelia are explicitly represented, they can be altered to simulate pathophysiological conditions and pharmacological interventions. The model serves as an appropriate starting point for simulations of physiological, pathophysiological, and pharmacological renal conditions and for exploring the relationship between the extrarenal environment and renal excretory function in physiological and pathophysiological contexts.
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Affiliation(s)
- Robert Moss
- Mathematics Dept., Duke Univ., Box 90320, Durham, NC 27708-0320.
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Abstract
The human kidneys produce approximately 160-170 L of ultrafiltrate per day. The proximal tubule contributes to fluid, electrolyte, and nutrient homeostasis by reabsorbing approximately 60%-70% of the water and NaCl, a greater proportion of the NaHCO3, and nearly all of the nutrients in the ultrafiltrate. The proximal tubule is also the site of active solute secretion, hormone production, and many of the metabolic functions of the kidney. This review discusses the transport of NaCl, NaHCO3, glucose, amino acids, and two clinically important anions, citrate and phosphate. NaCl and the accompanying water are reabsorbed in an isotonic fashion. The energy that drives this process is generated largely by the basolateral Na(+)/K(+)-ATPase, which creates an inward negative membrane potential and Na(+)-gradient. Various Na(+)-dependent countertransporters and cotransporters use the energy of this gradient to promote the uptake of HCO3 (-) and various solutes, respectively. A Na(+)-dependent cotransporter mediates the movement of HCO3 (-) across the basolateral membrane, whereas various Na(+)-independent passive transporters accomplish the export of various other solutes. To illustrate its homeostatic feat, the proximal tubule alters its metabolism and transport properties in response to metabolic acidosis. The uptake and catabolism of glutamine and citrate are increased during acidosis, whereas the recovery of phosphate from the ultrafiltrate is decreased. The increased catabolism of glutamine results in increased ammoniagenesis and gluconeogenesis. Excretion of the resulting ammonium ions facilitates the excretion of acid, whereas the combined pathways accomplish the net production of HCO3 (-) ions that are added to the plasma to partially restore acid-base balance.
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Affiliation(s)
- Norman P Curthoys
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado; and
| | - Orson W Moe
- Departments of Internal Medicine and Physiology, University of Texas Southwestern Medical Center, Dallas, Texas
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30
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Abstract
The kidney plays a fundamental role in maintaining body salt and fluid balance and blood pressure homeostasis through the actions of its proximal and distal tubular segments of nephrons. However, proximal tubules are well recognized to exert a more prominent role than distal counterparts. Proximal tubules are responsible for reabsorbing approximately 65% of filtered load and most, if not all, of filtered amino acids, glucose, solutes, and low molecular weight proteins. Proximal tubules also play a key role in regulating acid-base balance by reabsorbing approximately 80% of filtered bicarbonate. The purpose of this review article is to provide a comprehensive overview of new insights and perspectives into current understanding of proximal tubules of nephrons, with an emphasis on the ultrastructure, molecular biology, cellular and integrative physiology, and the underlying signaling transduction mechanisms. The review is divided into three closely related sections. The first section focuses on the classification of nephrons and recent perspectives on the potential role of nephron numbers in human health and diseases. The second section reviews recent research on the structural and biochemical basis of proximal tubular function. The final section provides a comprehensive overview of new insights and perspectives in the physiological regulation of proximal tubular transport by vasoactive hormones. In the latter section, attention is particularly paid to new insights and perspectives learnt from recent cloning of transporters, development of transgenic animals with knockout or knockin of a particular gene of interest, and mapping of signaling pathways using microarrays and/or physiological proteomic approaches.
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Affiliation(s)
- Jia L Zhuo
- Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
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31
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Parker MD, Boron WF. The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev 2013; 93:803-959. [PMID: 23589833 PMCID: PMC3768104 DOI: 10.1152/physrev.00023.2012] [Citation(s) in RCA: 208] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3 exchangers (AE1-3), five Na(+)-coupled HCO3(-) transporters (NCBTs), and two other unusual members (AE4, BTR1). In this review, we mainly focus on the five mammalian NCBTs-NBCe1, NBCe2, NBCn1, NDCBE, and NBCn2. Each plays a specialized role in maintaining intracellular pH and, by contributing to the movement of HCO3(-) across epithelia, in maintaining whole-body pH and otherwise contributing to epithelial transport. Disruptions involving NCBT genes are linked to blindness, deafness, proximal renal tubular acidosis, mental retardation, and epilepsy. We also review AE1-3, AE4, and BTR1, addressing their relevance to the study of NCBTs. This review draws together recent advances in our understanding of the phylogenetic origins and physiological relevance of NCBTs and their progenitors. Underlying these advances is progress in such diverse disciplines as physiology, molecular biology, genetics, immunocytochemistry, proteomics, and structural biology. This review highlights the key similarities and differences between individual NCBTs and the genes that encode them and also clarifies the sometimes confusing NCBT nomenclature.
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Affiliation(s)
- Mark D Parker
- Dept. of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4970, USA.
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32
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Bernstein KE, Ong FS, Blackwell WLB, Shah KH, Giani JF, Gonzalez-Villalobos RA, Shen XZ, Fuchs S, Touyz RM. A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme. Pharmacol Rev 2013; 65:1-46. [PMID: 23257181 PMCID: PMC3565918 DOI: 10.1124/pr.112.006809] [Citation(s) in RCA: 217] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors.
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Affiliation(s)
- Kenneth E Bernstein
- Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Davis 2021, Los Angeles, CA 90048, USA.
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Abstract
PURPOSE OF REVIEW Despite decades of study, the pathogenesis of essential hypertension remains obscure, but the kidney appears to play a central role. Technology for manipulation of the mouse genome has been immensely valuable in dissecting pathways involved in blood pressure control. This review summarizes recent studies employing this technology to understand signaling pathways and specific cell lineages within the kidney that are involved in the regulation of sodium excretion impacting blood pressure homeostasis. RECENT FINDINGS We review a series of recent studies of regulatory pathways affecting sodium excretion by the kidney including the renin-angiotensin system, the mineralocorticoid receptor, the endothelin system, nitric oxide, and the with-no-lysine (K)/sterile 20-like kinase pathway. We have specifically highlighted studies utilizing transgenic mouse models, which provide a powerful mechanism for defining the role of proteins and pathways on sodium balance and blood pressure in the intact organism. SUMMARY These studies underscore the importance of the kidney in regulation of blood pressure and the pathogenesis of hypertension. Transgenic mouse models provide a powerful approach to identifying key cell lineages and molecular pathways causing hypertension. These pathways represent potential targets for novel antihypertensive therapies.
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Ashek A, Menzies RI, Mullins LJ, Bellamy COC, Harmar AJ, Kenyon CJ, Flatman PW, Mullins JJ, Bailey MA. Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat. PLoS One 2012; 7:e36311. [PMID: 22558431 PMCID: PMC3338649 DOI: 10.1371/journal.pone.0036311] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 04/02/2012] [Indexed: 12/02/2022] Open
Abstract
Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP) rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ∼20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.
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Affiliation(s)
- Ali Ashek
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Robert I. Menzies
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Linda J. Mullins
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | | | - Anthony J. Harmar
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Christopher J. Kenyon
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Peter W. Flatman
- Centre for Integrative Physiology, The University of Edinburgh, Edinburgh, United Kingdom
| | - John J. Mullins
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Matthew A. Bailey
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
- * E-mail:
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Inoue BH, dos Santos L, Pessoa TD, Antonio EL, Pacheco BPM, Savignano FA, Carraro-Lacroix LR, Tucci PJF, Malnic G, Girardi ACC. Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am J Physiol Regul Integr Comp Physiol 2012; 302:R166-74. [DOI: 10.1152/ajpregu.00127.2011] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Heart failure (HF) is associated with a reduced effective circulating volume that drives sodium and water retention and extracellular volume expansion. We therefore hypothesized that Na+/H+ exchanger isoform 3 (NHE3), the major apical transcellular pathway for sodium reabsorption in the proximal tubule, is upregulated in an experimental model of HF. HF was induced in male rats by left ventricle radiofrequency ablation. Sham-operated rats (sham) were used as controls. At 6 wk after surgery, HF rats exhibited cardiac dysfunction with a dramatic increase in left ventricular end-diastolic pressure. By means of stationary in vivo microperfusion and pH-dependent sodium uptake, we demonstrated that NHE3 transport activity was significantly higher in the proximal tubule of HF compared with sham rats. Increased NHE3 activity was paralleled by increased renal cortical NHE3 expression at both protein and mRNA levels. In addition, the baseline PKA-dependent NHE3 phosphorylation at serine 552 was reduced in renal cortical membranes of rats with HF. Collectively, these results suggest that NHE3 is upregulated in the proximal tubule of HF rats by transcriptional, translational, and posttranslational mechanisms. Enhanced NHE3-mediated sodium reabsorption in the proximal tubule may contribute to extracellular volume expansion and edema, the hallmark feature of HF. Moreover, our study emphasizes the importance of undertaking a cardiorenal approach to contain progression of cardiac disease.
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Affiliation(s)
- Bruna H. Inoue
- Heart Institute (InCor), University of São Paulo Medical School
| | - Leonardo dos Santos
- Heart Institute (InCor), University of São Paulo Medical School
- Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, ES
| | - Thaissa D. Pessoa
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo; and
| | - Ednei L. Antonio
- Department of Physiology, Federal University of São Paulo, São Paulo, Brazil
| | | | | | | | - Paulo J. F. Tucci
- Department of Physiology, Federal University of São Paulo, São Paulo, Brazil
| | - Gerhard Malnic
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo; and
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Ellis B, Li XC, Miguel-Qin E, Gu V, Zhuo JL. Evidence for a functional intracellular angiotensin system in the proximal tubule of the kidney. Am J Physiol Regul Integr Comp Physiol 2011; 302:R494-509. [PMID: 22170616 DOI: 10.1152/ajpregu.00487.2011] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
ANG II is the most potent and important member of the classical renin-angiotensin system (RAS). ANG II, once considered to be an endocrine hormone, is now increasingly recognized to also play novel and important paracrine (cell-to-cell) and intracrine (intracellular) roles in cardiovascular and renal physiology and blood pressure regulation. Although an intracrine role of ANG II remains an issue of continuous debates and requires further confirmation, a great deal of research has recently been devoted to uncover the novel actions and elucidate underlying signaling mechanisms of the so-called intracellular ANG II in cardiovascular, neural, and renal systems. The purpose of this article is to provide a comprehensive review of the intracellular actions of ANG II, either administered directly into the cells or expressed as an intracellularly functional fusion protein, and its effects throughout a variety of target tissues susceptible to the impacts of an overactive ANG II, with a particular focus on the proximal tubules of the kidney. While continuously reaffirming the roles of extracellular or circulating ANG II in the proximal tubules, our review will focus on recent evidence obtained for the novel biological roles of intracellular ANG II in cultured proximal tubule cells in vitro and the potential physiological roles of intracellular ANG II in the regulation of proximal tubular reabsorption and blood pressure in rats and mice. It is our hope that the new knowledge on the roles of intracellular ANG II in proximal tubules will serve as a catalyst to stimulate further studies and debates in the field and to help us better understand how extracellular and intracellular ANG II acts independently or interacts with each other, to regulate proximal tubular transport and blood pressure in both physiological and diseased states.
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Affiliation(s)
- Brianne Ellis
- Laboratoory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA
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Deng J, Wang DX, Deng W, Li CY, Tong J, Ma H. Regulation of alveolar fluid clearance and ENaC expression in lung by exogenous angiotensin II. Respir Physiol Neurobiol 2011; 181:53-61. [PMID: 22138610 DOI: 10.1016/j.resp.2011.11.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2011] [Revised: 11/17/2011] [Accepted: 11/18/2011] [Indexed: 01/11/2023]
Abstract
Angiotensin II (Ang II) has been demonstrated as a pro-inflammatory effect in acute lung injury, but studies of the effect of Ang II on the formation of pulmonary edema and alveolar filling remains unclear. Therefore, in this study the regulation of alveolar fluid clearance (AFC) and the expression of epithelial sodium channel (ENaC) by exogenous Ang II was verified. SD rats were anesthetized and were given Ang II with increasing doses (1, 10 and 100 μg/kg per min) via osmotic minipumps, whereas control rats received only saline vehicle. AT1 receptor antagonist ZD7155 (10 mg/kg) and inhibitor of cAMP degeneration rolipram (1 mg/kg) were injected intraperitoneally 30 min before administration of Ang II. The lungs were isolated for measurement of alveolar fluid clearance. The mRNA and protein expression of ENaC were detected by RT-PCR and Western blot. Exposure to higher doses of Ang II reduced AFC in a dose-dependent manner and resulted in a non-coordinate regulation of α-ENaC vs. the regulation of β- and γ-ENaC, however Ang II type 1 (AT1) receptor antagonist ZD7155 prevented the Ang II-induced inhibition of fluid clearance and dysregulation of ENaC expression. In addition, exposure to inhibitor of cAMP degradation rolipram blunted the Ang II-induced inhibition of fluid clearance. These results indicate that through activation of AT(1) receptor, exogenous Ang II promotes pulmonary edema and alveolar filling by inhibition of alveolar fluid clearance via downregulation of cAMP level and dysregulation of ENaC expression.
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Affiliation(s)
- Jia Deng
- Department of Respiratory Medicine, Second Affiliated of Chongqing Medical University, Chongqing, China
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Bodor C, Nagy JP, Végh B, Németh A, Jenei A, MirzaHosseini S, Sebe A, Rosivall L. Angiotensin II increases the permeability and PV-1 expression of endothelial cells. Am J Physiol Cell Physiol 2011; 302:C267-76. [PMID: 22012329 DOI: 10.1152/ajpcell.00138.2011] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Angiotensin II (ANG II), the major effector molecule of the renin-angiotensin system (RAS), is a powerful vasoactive mediator associated with hypertension and renal failure. In this study the permeability changes and its morphological attributes in endothelial cells of human umbilical vein (HUVECs) were studied considering the potential regulatory role of ANG II. The effects of ANG II were compared with those of vascular endothelial growth factor (VEGF). Permeability was determined by 40 kDa FITC-Dextran and electrical impedance measurements. Plasmalemmal vesicle-1 (PV-1) mRNA levels were measured by PCR. Endothelial cell surface was studied by atomic force microscopy (AFM), and caveolae were visualized by transmission electron microscopy (TEM) in HUVEC monolayers. ANG II (10(-7) M), similarly to VEGF (100 ng/ml), increased the endothelial permeability parallel with an increase in the number of cell surface openings and caveolae. AT1 and VEGF-R2 receptor blockers (candesartan and ZM-323881, respectively) blunted these effects. ANG II and VEGF increased the expression of PV-1, which could be blocked by candesartan or ZM-323881 pretreatments and by the p38 mitogem-activated protein (MAP) kinase inhibitor SB-203580. Additionally, SB-203580 blocked the increase in endothelial permeability and the number of surface openings and caveolae. In conclusion, we have demonstrated that ANG II plays a role in regulation of permeability and formation of cell surface openings through AT1 receptor and PV-1 protein synthesis in a p38 MAP kinase-dependent manner in endothelial cells. The surface openings that increase in parallel with permeability may represent transcellular channels, caveolae, or both. These morphological and permeability changes may be involved in (patho-) physiological effects of ANG II.
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Affiliation(s)
- Csaba Bodor
- Hungarian Academy of Sciences and Semmelweis University, Research Group for Pediatrics and Nephrology, Institute of Pathophysiology, Semmelweis University, Faculty of Medicine, Budapest Hungary
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Javkhedkar AA, Lokhandwala MF, Banday AA. Defective nitric oxide production impairs angiotensin II-induced Na-K-ATPase regulation in spontaneously hypertensive rats. Am J Physiol Renal Physiol 2011; 302:F47-51. [PMID: 21900450 DOI: 10.1152/ajprenal.00270.2011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Angiotensin (ANG) II via ANG II type 1 receptors (AT1R) activates renal sodium transporters including Na-K-ATPase and regulates sodium homeostasis and blood pressure. It is reported that at a high concentration, ANG II either inhibits or fails to stimulate Na-K-ATPase. However, the mechanisms for these phenomena are not clear. Here, we identified the signaling molecules involved in regulation of renal proximal tubular Na-K-ATPase at high ANG II concentrations. Proximal tubules from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were incubated with low concentrations of ANG II (pM), which activated Na-K-ATPase in both the groups; however, the stimulation was more robust in SHR. A high concentration of ANG II (μM) failed to stimulate Na-K-ATPase in WKY rats. However, in SHR ANG II (μM) continued to stimulate Na-K-ATPase, which was sensitive to the AT1R antagonist candesartan. In the presence of N(G)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide (NO) synthase (NOS) inhibitor, ANG II (μM) caused stimulation of Na-K-ATPase in proximal tubules of WKY rats while having no further stimulatory effect in SHR. ANG II (μM), via AT1R, increased proximal tubular NO levels in WKY rats but not in SHR. In SHR, NOS was uncoupled as incubation of proximal tubules with ANG II and l-arginine, a NOS substrate, caused superoxide generation only in SHR and not in WKY rats. The superoxide production in SHR was sensitive to l-NAME. There was exaggerated proximal tubular AT1R-G protein coupling and NAD(P)H oxidase activation in response to ANG II (μM) in proximal tubules of SHR compared with WKY rats. In SHR, inhibition of NADPH oxidase restored NOS coupling and ANG II-induced NO accumulation. In conclusion, at a high concentration ANG II (μM) activates renal NO signaling, which prevents stimulation of Na-K-ATPase in WKY rats. However, in SHR ANG II (μM) overstimulates NADPH oxidase, which impairs the NO system and leads to continued Na-K-ATPase activation.
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Li XC, Zhuo JL. Phosphoproteomic analysis of AT1 receptor-mediated signaling responses in proximal tubules of angiotensin II-induced hypertensive rats. Kidney Int 2011; 80:620-32. [PMID: 21697807 PMCID: PMC3164930 DOI: 10.1038/ki.2011.161] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The signaling mechanisms underlying the effects of angiotensin II in proximal tubules of the kidney are not completely understood. Here we measured signal protein phosphorylation in isolated proximal tubules using pathway-specific proteomic analysis in rats continuously infused with pressor or non-pressor doses of angiotensin II over a 2-week period. Of the 38 phosphoproteins profiled, 14 were significantly altered by the pressor dose. This included increased phosphorylation of the protein kinase C isoenzymes, PKCα and PKCβII, and the glycogen synthase kinases, GSK3α and GSK3β. Phosphorylation of the cAMP-response element binding protein 1 and PKCδ were decreased, whereas PKCɛ remained unchanged. By contrast, the phosphorylation of only seven proteins was altered by the non-pressor dose, which increased that of PKCα, PKCδ, and GSKα. Phosphorylation of MAP kinases, ERK1/2, was not increased in proximal tubules in vivo by the pressor dose, but was in proximal tubule cells in vitro. Infusion of the pressor dose decreased, whereas the non-pressor dose of angiotensin II increased the phosphorylation of the sodium and hydrogen exchanger 3 (NHE-3) in membrane fractions of proximal tubules. Losartan largely blocked the signaling responses induced by the pressor dose. Thus, PKCα and PKCβII, GSK3α and GSK3β, and cAMP-dependent signaling pathways may have important roles in regulating proximal tubular sodium and fluid transport in Ang II-induced hypertensive rats.
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Affiliation(s)
- Xiao C Li
- Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, The University of Mississippi Medical Center, 1500 North State Street, Jackson, MS 39216, USA
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Li H, Weatherford ET, Davis DR, Keen HL, Grobe JL, Daugherty A, Cassis LA, Allen AM, Sigmund CD. Renal proximal tubule angiotensin AT1A receptors regulate blood pressure. Am J Physiol Regul Integr Comp Physiol 2011; 301:R1067-77. [PMID: 21753145 DOI: 10.1152/ajpregu.00124.2011] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
All components of the renin angiotensin system necessary for ANG II generation and action have been reported to be present in renal proximal convoluted tubules. Given the close relationship between renal sodium handling and blood pressure regulation, we hypothesized that modulating the action of ANG II specifically in the renal proximal tubules would alter the chronic level of blood pressure. To test this, we used a proximal tubule-specific, androgen-dependent, promoter construct (KAP2) to generate mice with either overexpression of a constitutively active angiotensin type 1A receptor transgene or depletion of endogenous angiotensin type 1A receptors. Androgen administration to female transgenic mice caused a robust induction of the transgene in the kidney and increased baseline blood pressure. In the receptor-depleted mice, androgen administration to females resulted in a Cre recombinase-mediated deletion of angiotensin type 1A receptors in the proximal tubule and reduced blood pressure. In contrast to the changes observed at baseline, there was no difference in the blood pressure response to a pressor dose of ANG II in either experimental model. These data, from two separate mouse models, provide evidence that ANG II signaling via the type 1A receptor in the renal proximal tubule is a regulator of systemic blood pressure under baseline conditions.
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Affiliation(s)
- Huiping Li
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA
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Metabolic programming during lactation stimulates renal Na+ transport in the adult offspring due to an early impact on local angiotensin II pathways. PLoS One 2011; 6:e21232. [PMID: 21747933 PMCID: PMC3128598 DOI: 10.1371/journal.pone.0021232] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 05/24/2011] [Indexed: 12/21/2022] Open
Abstract
Background Several studies have correlated perinatal malnutrition with diseases in adulthood, giving support to the programming hypothesis. In this study, the effects of maternal undernutrition during lactation on renal Na+-transporters and on the local angiotensin II (Ang II) signaling cascade in rats were investigated. Methodology/Principal Findings Female rats received a hypoproteic diet (8% protein) throughout lactation. Control and programmed offspring consumed a diet containing 20% protein after weaning. Programming caused a decrease in the number of nephrons (35%), in the area of the Bowman's capsule (30%) and the capillary tuft (30%), and increased collagen deposition in the cortex and medulla (by 175% and 700%, respectively). In programmed rats the expression of (Na++K+)ATPase in proximal tubules increased by 40%, but its activity was doubled owing to a threefold increase in affinity for K+. Programming doubled the ouabain-insensitive Na+-ATPase activity with loss of its physiological response to Ang II, increased the expression of AT1 and decreased the expression of AT2 receptors), and caused a pronounced inhibition (90%) of protein kinase C activity with decrease in the expression of the α (24%) and ε (13%) isoforms. Activity and expression of cyclic AMP-dependent protein kinase decreased in the same proportion as the AT2 receptors (30%). In vivo studies at 60 days revealed an increased glomerular filtration rate (GFR) (70%), increased Na+ excretion (80%) and intense proteinuria (increase of 400% in protein excretion). Programmed rats, which had normal arterial pressure at 60 days, became hypertensive by 150 days. Conclusions/Significance Maternal protein restriction during lactation results in alterations in GFR, renal Na+ handling and in components of the Ang II-linked regulatory pathway of renal Na+ reabsorption. At the molecular level, they provide a framework for understanding how metabolic programming of renal mechanisms contributes to the onset of hypertension in adulthood.
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Uchida T, Hayashi K, Kido H, Watanabe M. Diuretic Action of the Novel Loop Diuretic Torasemide in the Presence of Angiotensin II or Endothelin-1 in Anaesthetized Dogs. J Pharm Pharmacol 2011; 44:39-43. [PMID: 1350626 DOI: 10.1111/j.2042-7158.1992.tb14360.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Abstract
The effects of torasemide (0·1 and 1 mg kg−1, i.v.) and furosemide (3 mg kg−1) on renal haemodynamics and excretory responses in the presence of angiotensin II and endothelin-1 was examined in anaesthetized dogs. Angiotensin II or endothelin-1 was continuously infused into the renal artery throughout the experiment and a bolus of torasemide or furosemide was injected into the bracheal vein. Continuous intrarenal arterial (i.r.a.) infusion of angiotensin II, at a dose of 5 ng kg−1 min−1, increased renal vascular resistance (RVR) and decreased renal blood flow (RBF) and glomerular filtration rate (GFR), but had no effect on systemic mean arterial pressure (MAP). Urinary excretion of sodium (UNaV) and urine flow (UF) were significantly decreased during angiotensin II infusion. Intravenous injections of torasemide in the presence of angiotensin II caused a dose-dependent increase in UF, UNaV and urinary excretion of potassium (UKV), while a decrease in RVR was accompanied by an increase in RBF. UKV was greater in the furosemide group than in the torasemide group, despite both groups having the same degree of aquaresis and natriuresis. Continuous i.r.a. infusion of endothelin-1, 1·5 ng kg−1 min−1, produced effects similar to those of angiotensin II on renal haemodynamics; however, the onset of action was extremely slow compared with the effects produced by angiotensin II. Endothelin-1 caused a significant decrease in UF, UNaV and UKV only at a later period, despite a relatively early depression of renal haemodynamics. Torasemide and furosemide also produced a sufficient diuretic action in this model. Overall, kaliuresis was greater in the furosemide group than in the torasemide group. The present study demonstrates that torasemide exhibited a significant diuretic action in the angiotensin II- or endothelin-1 -induced renal impairment model, with less kaliuresis than furosemide at a concentration which caused the same degree of natriuresis.
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Affiliation(s)
- T Uchida
- Central Research Laboratory, Green Cross Corporation, Osaka, Japan
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Li C, Wang W, Rivard CJ, Lanaspa MA, Summer S, Schrier RW. Molecular mechanisms of angiotensin II stimulation on aquaporin-2 expression and trafficking. Am J Physiol Renal Physiol 2011; 300:F1255-61. [PMID: 21325494 DOI: 10.1152/ajprenal.00469.2010] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
ANG II plays a major role in renal water and sodium regulation. In the immortalized mouse renal collecting duct principal cells (mpkCCD(cl4)) cell line, we treated cells with ANG II and examined aquaporin-2 (AQP2) protein expression, trafficking, and mRNA levels, by immunoblotting, immunofluorescence, and RT-PCR. After 24-h incubation, ANG II-induced AQP2 protein expression was observed at the concentration of 10(-10) M and increased in a dose-dependent manner. ANG II (10(-7) M) increased AQP2 protein expression and mRNA levels at 0.5, 1, 2, 6, and 24 h. Immunofluorescence studies showed that ANG II increased the apical membrane targeting of AQP2 from 30 min to 6 h. Next, the signaling pathways underlying the ANG II-induced AQP2 expression were investigated. The PKC inhibitor Ro 31-8220 (5 × 10(-6) M) and the PKA inhibitor H89 (10(-5) M) blocked ANG II-induced AQP2 expression, respectively. Calmodulin inhibitor W-7 markedly reduced ANG II- and/or dDAVP-stimulated AQP2 expression. ANG II (10(-9) M) and/or dDAVP (10(-10) M) stimulated AQP2 protein levels and cAMP accumulation, which was completely blocked by pretreatment with the vasopressin V2 receptor (V2R) antagonist SR121463B (10(-8) M). Pretreatment with the angiotensin AT(1) receptor (AT1R) antagonist losartan (3 × 10(-6) M) blocked ANG II (10(-9) M)-stimulated AQP2 protein expression and cAMP accumulation, and partially blocked dDAVP (10(-10) M)- and dDAVP+ANG II-induced AQP2 protein expression and cAMP accumulation. In conclusion, ANG II regulates AQP2 protein, trafficking, and gene expression in renal collecting duct principal cells. ANG II-induced AQP2 expression involves cAMP, PKC, PKA, and calmodulin signaling pathways via V2 and AT(1) receptors.
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Affiliation(s)
- Chunling Li
- Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado, USA
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Laragh JH, Sealey JE. Renin–Angiotensin–Aldosterone System and the Renal Regulation of Sodium, Potassium, and Blood Pressure Homeostasis. Compr Physiol 2011. [DOI: 10.1002/cphy.cp080231] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Harris PJ, Hiranyachattada S, Antoine AM, Walker L, Reilly AM, Eitle E. Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: REGULATION OF RENAL TUBULAR SODIUM TRANSPORT BY ANGIOTENSIN II AND ATRIAL NATRIURETIC FACTOR. Clin Exp Pharmacol Physiol 2010; 23 Suppl 3:S112-8. [DOI: 10.1111/j.1440-1681.1996.tb03071.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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He P, Klein J, Yun CC. Activation of Na+/H+ exchanger NHE3 by angiotensin II is mediated by inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with IP3 (IRBIT) and Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 2010; 285:27869-78. [PMID: 20584908 DOI: 10.1074/jbc.m110.133066] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Angiotensin II (ANG II) stimulates renal tubular reabsorption of NaCl by targeting Na(+)/H(+) exchanger NHE3. We have shown previously that inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) plays a critical role in stimulation of NHE3 in response to elevated intracellular Ca(2+) concentration ([Ca(2+)](i)). In this study, we investigated the role of IRBIT in mediating NHE3 activation by ANG II. IRBIT is abundantly expressed in the proximal tubules where NHE3 is located. ANG II at physiological concentrations stimulates NHE3 transport activity in a model proximal tubule cell line. ANG II-induced activation of NHE3 was abrogated by knockdown of IRBIT, whereas overexpression of IRBIT enhanced the effect of ANG II on NHE3. ANG II transiently increased binding of IRBIT to NHE3 at 5 min but became dissociated by 45 min. In comparison, it took at least 15 min of ANG II treatment for an increase in NHE3 activity and NHE3 surface expression. The stimulation of NHE3 by ANG II was dependent on changes in [Ca(2+)](i) and Ca(2+)/calmodulin-dependent protein kinases II. Inhibition of CaMKII completely blocked the ANG II-induced binding of IRBIT to NHE3 and the increase in NHE3 surface abundance. Several serine residues of IRBIT are thought to be important for IRBIT binding. Mutations of Ser-68, Ser-71, and Ser-74 of IRBIT decreased binding of IRBIT to NHE3 and its effect on NHE3 activity. In conclusion, our current findings demonstrate that IRBIT is critically involved in mediating activation of NHE3 by ANG II via a Ca(2+)/calmodulin-dependent protein kinases II-dependent pathway.
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Affiliation(s)
- Peijian He
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30324, USA
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Dagan A, Gattineni J, Habib S, Baum M. Effect of prenatal dexamethasone on postnatal serum and urinary angiotensin II levels. Am J Hypertens 2010; 23:420-4. [PMID: 20075846 DOI: 10.1038/ajh.2009.274] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Prenatal programming of hypertension has been described in humans and in animal models that receive a prenatal insult, but the mechanism for the increase in blood pressure remains elusive. METHODS In male rats whose mothers received dexamethasone between days 15 and 18 of gestation systemic and urinary levels of angiotensin II were measured to determine whether angiotensin II was a potential factor for the generation (4 weeks of age) or maintenance (8 weeks of age) of hypertension. RESULTS A group 4- and 8-week-old male rats that were the product of a pregnancy where the mother received prenatal dexamethasone between days 15 and 18 of gestation had comparable plasma renin and angiotensin II levels to the offspring of vehicle-treated controls. Renal angiotensin II levels were not different at 4 and 8 weeks of age between the controls and the prenatal dexamethasone group. Urine angiotensin II/Creatinine levels, a reflection of filtered and renally generated and secreted angiotensin II, were higher at both 4 and 8 weeks of age in male rats that received prenatal dexamethasone compared to controls. CONCLUSIONS The high-urine angiotensin II levels in prehypertensive and hypertensive rats that were the product of mothers that received dexamethasone compared to vehicle suggest that luminal angiotensin II may play a role in the generation and maintenance of hypertension in this model of prenatal programming.
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