Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT1a/MAPK/NF-кB signaling pathways

Long-term angiotensin II (ANG II) infusion significantly increases ANG II levels in the kidney through two major mechanisms: AT1 receptor-mediated augmentation of angiotensinogen (AGT) expression and uptake of circulating ANG II by the proximal tubules. However, it is not known whether intracellular ANG II stimulates AGT expression in the proximal tubule. In the present study, we overexpressed an intracellular cyan fluorescent ANG II fusion protein (Ad-sglt2-ECFP/ANG II) selectively in the proximal tubule of rats and mice using the sodium and glucose cotransporter 2 (sglt2) promoter. AGT mRNA and protein expression in the renal cortex and 24-h urinary AGT excretion were determined 4 wk following overexpression of ECFP/ANG II in the proximal tubule. Systolic blood pressure was significantly increased with a small antinatriuretic effect in rats and mice with proximal tubule-selective expression of ECFP/ANG II ( P < 0.01). AGT mRNA and protein expression in the cortex were increased by >1.5-fold and 61 ± 16% ( P < 0.05), whereas urinary AGT excretion was increased from 48.7 ± 5.7 ( n = 13) to 102 ± 13.5 ( n = 13) ng/24 h ( P < 0.05). However, plasma AGT, renin activity, and ANG II levels remained unaltered by ECFP/ANG II. The increased AGT mRNA and protein expressions in the cortex by ECFP/ANG II were blocked in AT1a-knockout (KO) mice. Studies in cultured mouse proximal tubule cells demonstrated involvement of AT1a receptor/MAP kinases/NF-кB signaling pathways. These results indicate that intracellular ANG II stimulates AGT expression in the proximal tubules, leading to increased AGT formation and secretion into the tubular fluid, which contributes to ANG II-dependent hypertension.

Download Full-text

Novel signaling mechanisms of intracellular angiotensin II-induced NHE3 expression and activation in mouse proximal tubule cells

AJP Renal Physiology ◽

10.1152/ajprenal.00219.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. F1617-F1628 ◽

Cited By ~ 25

Author(s):

X. C. Li ◽

U. Hopfer ◽

J. L. Zhuo

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Signaling Pathways ◽

Map Kinases ◽

Proximal Tubules ◽

Sodium Reabsorption ◽

Ang Ii ◽

Proximal Tubule Cells ◽

Tubule Cells

Expression of a cytosolic cyan fluorescent fusion protein of angiotensin II (ECFP/ANG II) in proximal tubules increases blood pressure in rodents. To determine cellular signaling pathways responsible for this response, we expressed ECFP/ANG II in transport-competent mouse proximal convoluted tubule cells (mPCT) from wild-type (WT) and type 1a ANG II receptor-deficient (AT1a-KO) mice and measured its effects on intracellular ANG II levels, surrogates of Na/H exchanger 3 (NHE3)-dependent Na+ absorption, as well as MAP kinases and NF-κB signaling. In WT mPCT cells, ECFP/ANG II expression doubled ANG II levels, increased NHE3 expression and membrane phospho-NHE3 proteins threefold and intracellular Na+ concentration by 65%. These responses were associated with threefold increases in phospho-ERK 1/2 and phospho-p38 MAPK, fivefold increases in p65 subunit of NF-κB, and threefold increases in phospho-IKKα/β (Ser 176/180) proteins. These signaling responses to ECFP/ANG II were inhibited by losartan (AT1 blocker), PD123319 (AT2 blocker), U0126 (MEK1/MEK2 inhibitor), and RO 106–9920 (NF-κB inhibitor). In mPCT cells of AT1a-KO mice, ECFP/ANG II also increased the levels of NHE3, p-ERK1/2, and p65 proteins above their controls, but considerably less so than in WT cells. In WT mice, selective expression of ECFP/ANG II in vivo in proximal tubules significantly increased blood pressure and indices of sodium reabsorption, in particular levels of phosphorylated NHE3 protein in the membrane fraction and proton gradient-stimulated 22Na+ uptake by proximal tubules. We conclude that intracellular ANG II may induce NHE3 expression and activation in mPCTs via AT1a- and AT2 receptor-mediated activation of MAP kinases ERK 1/2 and NF-κB signaling pathways.

Download Full-text

AT1 receptor-mediated uptake of angiotensin II and NHE-3 expression in proximal tubule cells through a microtubule-dependent endocytic pathway

AJP Renal Physiology ◽

10.1152/ajprenal.90734.2008 ◽

2009 ◽

Vol 297 (5) ◽

pp. F1342-F1352 ◽

Cited By ~ 42

Author(s):

Xiao C. Li ◽

Ulrich Hopfer ◽

Jia L. Zhuo

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Map Kinases ◽

Endocytic Pathway ◽

Dependent Manner ◽

Ang Ii ◽

Cellular Mechanisms ◽

Proximal Tubule Cells ◽

Associated Proteins ◽

Transferrin Uptake

Angiotensin II (ANG II) is taken up by proximal tubule (PT) cells via AT1 (AT1a) receptor-mediated endocytosis, but the underlying cellular mechanisms remain poorly understood. The present study tested the hypothesis that the microtubule- rather than the clathrin-dependent endocytic pathway regulates AT1-mediated uptake of ANG II and ANG II-induced sodium and hydrogen exchanger-3 (NHE-3) expression in PT cells. The expression of AT1 receptors, clathrin light (LC) and heavy chain (HC) proteins, and type 1 microtubule-associated proteins (MAPs; MAP-1A and MAP-1B) in PT cells were knocked down by their respective small interfering (si) RNAs before AT1-mediated FITC-ANG II uptake and ANG II-induced NHE-3 expression were studied. AT1 siRNAs inhibited AT1 expression and blocked ANG II-induced NHE-3 expression in PT cells, as expected ( P < 0.01). Clathrin LC or HC siRNAs knocked down their respective proteins by ∼90% with a peak response at 24 h, and blocked the clathrin-dependent uptake of Alexa Fluor 594-transferrin ( P < 0.01). However, neither LC nor HC siRNAs inhibited AT1-mediated uptake of FITC-ANG II or affected ANG II-induced NHE-3 expression. MAP-1A or MAP-1B siRNAs markedly knocked down MAP-1A or MAP-1B proteins in a time-dependent manner with peak inhibitions at 48 h (>76.8%, P < 0.01). MAP protein knockdown resulted in ∼52% decreases in AT1-mediated FITC-ANG II uptake and ∼66% decreases in ANG II-induced NHE-3 expression ( P < 0.01). These effects were associated with threefold decreases in ANG II-induced MAP kinases ERK 1/2 activation ( P < 0.01), but not with altered AT1 expression or clathrin-dependent transferrin uptake. Both losartan and AT1a receptor deletion in mouse PT cells completely abolished the effects of MAP-1A knockdown on ANG II-induced NHE-3 expression and activation of MAP kinases ERK1/2. Our findings suggest that the alternative microtubule-dependent endocytic pathway, rather than the canonical clathrin-dependent pathway, plays an important role in AT1 (AT1a)-mediated uptake of extracellular ANG II and ANG II-induced NHE-3 expression in PT cells.

Download Full-text

Intrarenal transfer of an intracellular fluorescent fusion of angiotensin II selectively in proximal tubules increases blood pressure in rats and mice

AJP Renal Physiology ◽

10.1152/ajprenal.00329.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. F1076-F1088 ◽

Cited By ~ 37

Author(s):

Xiao C. Li ◽

Julia L. Cook ◽

Isabelle Rubera ◽

Michel Tauc ◽

Fan Zhang ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Proximal Tubule ◽

Sodium Excretion ◽

Proximal Tubules ◽

Sodium Reabsorption ◽

Ang Ii ◽

Contralateral Kidney ◽

Adenoviral Transfer ◽

Rats And Mice

The present study tested the hypothesis that intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of angiotensin II (ECFP/ANG II) selectively in proximal tubules of the kidney increases blood pressure by activating AT1 (AT1a) receptors. Intrarenal transfer of ECFP/ANG II was induced in the superficial cortex of rat and mouse kidneys, and the sodium and glucose cotransporter 2 (sglt2) promoter was used to drive ECFP/ANG II expression selectively in proximal tubules. Intrarenal transfer of ECFP/ANG II induced a time-dependent, proximal tubule-selective expression of ECFP/ANG II in the cortex, which peaked at 2 wk and was sustained for 4 wk. ECFP/ANG II expression was low in the glomeruli and the entire medulla and was absent in the contralateral kidney or extrarenal tissues. At its peak of expression in proximal tubules at day 14, ANG II was increased by twofold in the kidney ( P < 0.01) and more than threefold in proximal tubules ( P < 0.01), but remained unchanged in plasma or urine. Systolic blood pressure was increased in ECFP/ANG II-transferred rats by 28 ± 6 mmHg ( P < 0.01), whereas fractional sodium excretion was decreased by 20% ( P < 0.01) and fractional lithium excretion was reduced by 24% ( P < 0.01). These effects were blocked by losartan and prevented in AT1a knockout mice. Transfer of a scrambled ECFP/ANG IIc had no effects on blood pressure, kidney, and proximal tubule ANG II, or sodium excretion. These results provide evidence that proximal tubule-selective transfer of an intracellular ANG II fusion protein increases blood pressure by activating AT1a receptors and increasing sodium reabsorption in proximal tubules.

Download Full-text

Abstract 405: Novel Signaling Mechanisms by Which Intracellular Angiotensin II Induces Na + /HCO 3 - CotransporterExpression In The Proximal Tubule of The Kidney

Hypertension ◽

10.1161/hyp.64.suppl_1.405 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Xiao C Li ◽

Julia L Cook ◽

Ulrich Hopfer ◽

Jia L Zhuo

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Signaling Pathways ◽

Map Kinases ◽

Ang Ii ◽

Wild Type ◽

Bicarbonate Reabsorption ◽

Signaling Mechanisms ◽

Proximal Tubular ◽

Deficient Mice

Previous studies have shown that endocrine and/or paracrine angiotensin II (ANG II) plays an important role in the regulation of sodium and bicarbonate reabsorption in the proximal tubule of the kidney. However, it is not known whether intracellular (or intracrine) ANG II also plays a role in these responses in the proximal tubule. The present study tested the hypothesis that overexpression of an intracellular cyan fluorescent fusion protein of ANG II (ECFP/ANG II) in the proximal tubule of the kidney induces the expression of the Na + /HCO 3 - cotransporter via MAPK- and NF-kB signaling pathways. To test the hypothesis, transport-competent mPCTs from wild-type and type 1a ANG II receptor-deficient mice (AT 1a -KO) were transfected with ECFP/ANG II, and treated with the AT 1 receptor blocker losartan, the MEK1/MEK2 inhibitor U0126, or the NF-κB inhibitor RO 106-9920. In wild-type mPCT cells, the expression of ECFP/ANG II more than doubled total and/or phosphorylated NHE3 antiporter and Na + /HCO 3 - cotransporter proteins (p<0.01). These response were accompanied by more than threefold increases in phospho-ERK 1/2, p65 subunit of NF-κB, and phospho-IKKα/β (Ser 176/180) proteins (p<0.01). Pretreatment of mPCT cells with losartan, U0126, or RO 106-9920 significantly blocked the effects of ECFP/ANG II (p<0.01). Furthermore, the effects of ECFP/ANG II were significantly attenuated in mPCT cells of AT 1a -KO mice (p<0.01),. In wild-type C57BL/6J mice, adenovirus-mediated overexpression of ECFP/ANG II selectively in the proximal tubule of the kidney, driven by the sodium and glucose cotransporter 2 (sglt2) promoter, significantly increased blood pressure, total and/or phosphorylated NHE3 and Na + /HCO 3 - proteins, and proximal tubular lithium reabsorption (p<0.01). These responses to ECFP/ANG II as observed in C57BL/6J mice were also attenuated in AT 1a -KO mice (p<0.01). Our results strongly suggest that intracellular ANG II may induce NHE3 and Na + /HCO 3 - expression, and increase proximal tubular sodium and bicarbonate reabsorption via AT 1a receptor-mediated activation of MAP kinases ERK 1/2 and NF-κB signaling pathways.

Download Full-text

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 ◽

10.1161/hypertensionaha.120.16336 ◽

2021 ◽

Author(s):

Xiao Chun Li ◽

Ana Paula Oliveira Leite ◽

Xiaowen Zheng ◽

Chunling Zhao ◽

Xu Chen ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Fusion Protein ◽

Proximal Tubule ◽

Proximal Tubules ◽

Normal Blood ◽

Ang Ii ◽

Normal Blood Pressure ◽

Wild Type ◽

Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

Download Full-text

Abstract 065: Overexpression of an Intracellular Angiotensin II Fusion Protein Selectively in the Mitochondria of the Proximal Tubules Elevates Blood Pressure in Mice via AT 1a Receptor-mediated Mitochondrial Respiratory and Glycolysis Stress

Hypertension ◽

10.1161/hyp.68.suppl_1.065 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Xiao C Li ◽

Manoocher Soleimani ◽

Hoang Nguyen ◽

Hong Li ◽

Jia L Zhuo

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Fusion Protein ◽

Proximal Tubule ◽

Physiological Role ◽

Proximal Tubules ◽

Ang Ii ◽

Stress Tests ◽

Arterial Blood ◽

Mitochondrial Respiratory

An intracrine mitochondrial renin-angiotensin system (RAS) has recently been identified in various animal and human tissues, but whether the mitochondrial RAS plays a physiological role in the regulation of blood pressure remains unknown. The present study tested whether overexpression of an intracellular angiotensin II fusion protein, ECFP/ANG II, selectively in the mitochondria of the proximal tubules alters blood pressure, and whether the effects may involve AT 1a receptors and the Na + /H + exchanger 3 (NHE3). An adenoviral vector encoding ECFP/ANG II, a mitochondria targeting sequence, and the sglt2 promoter, Ad-sglt2-mito-ECFP/ANG II, was constructed for proximal tubule- and mitochondria-specific overexpression for 2 weeks. In adult male C57BL/6J mice, overexpression of mito-ECFP/ANG II in the mitochondria of the proximal tubules increased systolic blood pressure (SBP) significantly (Control: 116 ± 3 vs. mito-ECFP/ANG II: 128 ± 3 mmHg; p <0.01, n=15). The blood pressure-increasing effect of Ad-sglt2-mito-ECFP/ANG II was blocked in proximal tubule-specific AT 1a -KO mice (Control: 105 ± 2 vs. mito-ECFP/ANG II: 104 ± 4 mmHg; n.s ., n=7), or in proximal tubule-specific NHE3-KO mice (Control: 108 ± 3 vs. mito-ECFP/ANG II: 107 ± 3 mmHg; n.s ., n=13), respectively. In further experiments, mouse proximal tubule cells were transfected with Ad-sglt2-mito-ECFP/ANG II for 48 h and treated with the AT 1 blocker losartan (10 μM) or the AT 2 blocker PD123319 (10 μM) to measure mitochondrial respiratory and glycolytic function using Seahorse XF Cell Mito and XF Glycolysis Stress Tests. The mito-ECFP/ANG II expression was robust and colocalized with MitoTracker® Red FM. Overexpression of mito-ECFP/ANG II markedly increased oxygen consumption rate (OCR) (Control: 139.4 ± 9.2 vs. mito-ECFP/ANG II: 236.3 ± 12.6 pmol/min; p <0.01, n=12) and extracellular acidification rate (ECAR) (Control: 8.8 ± 0.6 vs. mito-ECFP/ANG II: 11.8 ± 1.2 mpH/min; p <0.01, n=12), respectively. Losartan blocked the effects of mito-ECFP/ANG II on OCR and ECAR, whereas PD123319 had no effect. We conclude that intracellular ANG II may activate AT 1 receptors in the mitochondria of the proximal tubules to alter mitochondrial respiratory and glycolytic function and arterial blood pressure.

Download Full-text

Angiotensin II-dependent proximal tubule sodium transport requires receptor-mediated endocytosis

AJP Cell Physiology ◽

10.1152/ajpcell.1994.266.3.c669 ◽

1994 ◽

Vol 266 (3) ◽

pp. C669-C675 ◽

Cited By ~ 41

Author(s):

J. R. Schelling ◽

S. L. Linas

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Receptor Internalization ◽

Ang Ii ◽

Na Transport ◽

Cellular Mechanisms ◽

Transport Pathways ◽

Proximal Tubule Cells ◽

Receptor Mediated Endocytosis ◽

Tubule Cells

Angiotensin II (ANG II) receptors are present on apical and basolateral surfaces of proximal tubule cells. To determine the cellular mechanisms of proximal tubule ANG II receptor-mediated Na transport, apical-to-basolateral 22Na flux was measured in cultured proximal tubule cells. Apical ANG II caused increases in 22Na flux (maximum response: 100 nM, 30 min). Basolateral ANG II resulted in 22Na flux that was 23-56% greater than 22Na flux observed with equimolar apical ANG II. Apical ANG II-induced 22Na flux was prevented by preincubation with amiloride, ouabain, and the AT1 receptor antagonist losartan. Because apical ANG II signaling was previously shown to be endocytosis dependent, we questioned whether endocytosis was required for ANG II-stimulated proximal tubule Na transport as well. Apical (but not basolateral) ANG II-dependent 22Na flux was inhibited by phenylarsine oxide, an agent which prevents ANG II receptor internalization. In conclusion, apical and basolateral ANG II caused proximal tubule Na transport. Apical ANG II-dependent Na flux was mediated by AT1 receptors, transcellular transport pathways, and receptor-mediated endocytosis.

Download Full-text

Dietary fructose enhances angiotensin II-stimulated Na+ transport via activation of PKC-α in renal proximal tubules

AJP Renal Physiology ◽

10.1152/ajprenal.00543.2019 ◽

2020 ◽

Vol 318 (6) ◽

pp. F1513-F1519

Author(s):

Nianxin Yang ◽

Nancy J. Hong ◽

Jeffrey L. Garvin

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Tap Water ◽

Renal Proximal Tubule ◽

Proximal Tubules ◽

Control Group ◽

Ang Ii ◽

Dietary Fructose ◽

Intracellular Ca ◽

Pkc Β

Angiotensin II (ANG II) stimulates proximal nephron transport via activation of classical protein kinase C (PKC) isoforms. Acute fructose treatment stimulates PKC and dietary fructose enhances ANG II’s ability to stimulate Na+ transport, but the mechanisms are unclear. We hypothesized that dietary fructose enhances ANG II’s ability to stimulate renal proximal tubule Na+ reabsorption by augmenting PKC-α activation and increases in intracellular Ca2+. We measured total and isoform-specific PKC activity, basal and ANG II-stimulated oxygen consumption, a surrogate of Na+ reabsorption, and intracellular Ca2+ in proximal tubules from rats given either 20% fructose in their drinking water (fructose group) or tap water (control group). Total PKC activity was measured by ELISA. PKC-α, PKC-β, and PKC-γ activities were assessed by measuring particulate-to-soluble ratios. Intracelluar Ca2+ was measured using fura 2. ANG II stimulated total PKC activity by 53 ± 15% in the fructose group but not in the control group (−15 ± 11%, P < 0.002). ANG II stimulated PKC-α by 0.134 ± 0.026 but not in the control group (−0.002 ± 0.020, P < 0.002). ANG II increased PKC-γ activity by 0.008 ± 0.003 in the fructose group but not in the control group ( P < 0.046). ANG II did not stimulate PKC-β in either group. ANG II increased Na+ transport by 454 ± 87 nmol·min−1·mg protein−1 in fructose group, and the PKC-α/β inhibitor Gö6976 blocked this increase (−96 ± 205 nmol·min−1·mg protein−1, P < 0.045). ANG II increased intracellular Ca2+ by 148 ± 53 nM in the fructose group but only by 43 ± 10 nM in the control group ( P < 0.035). The intracellular Ca2+ chelator BAPTA blocked the ANG II-induced increase in Na+ transport in the fructose group. We concluded that dietary fructose enhances ANG II’s ability to stimulate renal proximal tubule Na+ reabsorption by augmenting PKC-α activation via elevated increases in intacellular Ca2+.

Download Full-text

Interleukin-6 stimulates α-MG uptake in renal proximal tubule cells: involvement of STAT3, PI3K/Akt, MAPKs, and NF-κB

AJP Renal Physiology ◽

10.1152/ajprenal.00034.2007 ◽

2007 ◽

Vol 293 (4) ◽

pp. F1036-F1046 ◽

Cited By ~ 22

Author(s):

Yu Jin Lee ◽

Jung Sun Heo ◽

Han Na Suh ◽

Min Young Lee ◽

Ho Jae Han

Keyword(s):

Protein Expression ◽

Proximal Tubule ◽

Signaling Pathways ◽

Interleukin 6 ◽

Renal Proximal Tubule ◽

Expression Level ◽

Protein Expression Level ◽

Proximal Tubule Cells ◽

Tubule Cells ◽

Renal Proximal Tubule Cells

Recent studies have shown that interleukin 6 (IL-6) acts on the cellular proliferation-activating transduction signals during cellular regeneration. Therefore, this study examined the effect of IL-6 on the activation of Na+/glucose cotransporters (SGLTs) and its related signaling pathways in primary cultured renal proximal tubule cells (PTCs). IL-6 increased the level of α-methyl-d-[14C]glucopyranoside (α-MG) uptake in time- and dose-dependent manners. IL-6 also increased SGLT1 plus SGLT2 mRNA and protein expression level. The IL-6 receptors (IL-6Rα and gp130) were expressed in PTCs. In addition, genistein and herbimycin A completely blocked the IL-6-induced increases in α-MG uptake and the protein expression level of SGLTs. On the other hand, IL-6 increased the level of 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate-sensitive cellular reactive oxygen species (ROS), and IL-6-induced increases in α-MG uptake and the protein expression level of SGLTs were blocked by ascorbic acid or taurine (antioxidants). IL-6 also increased the phosphorylation of signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) in a time-dependent manner. A pretreatment with STAT3 inhibitor LY 294002, an Akt inhibitor, or MAPK inhibitors significantly blocked the IL-6-induced increase in α-MG uptake. In addition, IL-6 increased the level of nuclear factor-κB (NF-κB) phosphorylation. A pretreatment with SN50 or BAY 11-7082 also blocked the IL-6-induced increase in α-MG uptake. In conclusion, IL-6 increases the SGLT activity through ROS, and its action in renal PTCs is associated with the STAT3, PI3K/Akt, MAPKs, and NF-κB signaling pathways.

Download Full-text

Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

Physiological Genomics ◽

10.1152/physiolgenomics.00122.2018 ◽

2019 ◽

Vol 51 (4) ◽

pp. 97-108 ◽

Cited By ~ 3

Author(s):

Xiao C. Li ◽

Xiaowen Zheng ◽

Xu Chen ◽

Chunling Zhao ◽

Dongmin Zhu ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Proximal Tubule ◽

Proximal Tubules ◽

Ang Ii ◽

Pressure Regulation ◽

Blood Pressure Homeostasis ◽

Induced Hypertension ◽

Basal Blood Pressure

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

Download Full-text