Search for other papers by M. Nakamura in
Current site
Google Scholar
PubMed
Search for other papers by N. Satoh in
Current site
Google Scholar
PubMed
Search for other papers by H. Tsukada in
Current site
Google Scholar
PubMed
Search for other papers by T. Mizuno in
Current site
Google Scholar
PubMed
Search for other papers by W. Fujii in
Current site
Google Scholar
PubMed
Department of Nephrology, Japan Community Health care Organization (JCHO), Tokyo Yamate Medical Center,
Search for other papers by A. Suzuki in
Current site
Google Scholar
PubMed
Search for other papers by S. Horita in
Current site
Google Scholar
PubMed
Search for other papers by M. Nangaku in
Current site
Google Scholar
PubMed
Search for other papers by M. Suzuki in
Current site
Google Scholar
PubMed
Abstract
Purpose
Acid-base transport in renal proximal tubules (PTs) is mainly sodium-dependent and conducted in coordination by the apical Na+/H+ exchanger (NHE3), vacuolar H+-adenosine triphosphatase (V-ATPase), and the basolateral Na+/HCO3- cotransporter. V-ATPase on PTs is well-known to play an important role in proton excretion. Recently we reported a stimulatory effect of insulin on these transporters. However, it is unclear whether insulin is involved in acid-base balance in PTs. Thus, we assessed the role of insulin in acid-base balance in PTs.
Methods
V-ATPase activity was evaluated using freshly isolated PTs obtained from mice, and specific inhibitors were then used to assess the signaling pathways involved in the observed effects.
Results
V-ATPase activity in PTs was markedly enhanced by insulin, and its activation was completely inhibited by bafilomycin (a V-ATPase-specific inhibitor), Akt inhibitor VIII, and PP242 (an mTORC1/2 inhibitor), but not by rapamycin (an mTORC1 inhibitor). V-ATPase activity was stimulated by 1 nm insulin by approximately 20% above baseline, which was completely suppressed by Akt1/2 inhibitor VIII. PP242 completely suppressed the insulin-mediated V-ATPase stimulation in mouse PTs, whereas rapamycin failed to influence the effect of insulin. Insulin-induced Akt phosphorylation in the mouse renal cortex was completely suppressed by Akt1/2 inhibitor VIII and PP242, but not by rapamycin.
Conclusion
Our results indicate that stimulation of V-ATPase activity by insulin in PTs is mediated via the Akt2/mTORC2 pathway. These results reveal the mechanism underlying the complex signaling in PT acid-base balance, providing treatment targets for renal disease.
-
1.
Rajkumar P, Pluznick JL. Acid-base regulation in the renal proximal tubules: using novel pH sensors to maintain homeostasis. Am J Physiol Renal Physiol 2018; 315: F1187–90.
-
2.
Mayor S. Low blood levels of bicarbonate are linked to premature death in healthy older people, study shows. BMJ 2016; 352: i172.
-
3.
Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Wehbe E, Raina R, et al.. Serum bicarbonate and mortality in stage 3 and stage 4 chronic kidney disease. Clin J Am Soc Nephrol 2011; 6: 2395–402.
-
4.
Raphael KL, Murphy RA, Shlipak MG, Satterfield S, Huston HK, Sebastian A, et al.. Bicarbonate concentration, acid-base status, and mortality in the health, aging, and body composition study. Clin J Am Soc Nephrol 2016; 11: 308–16.
-
5.
Lay AC, Hurcombe JA, Betin VMS, Barrington F, Rollason R, Ni L, et al.. Prolonged exposure of mouse and human podocytes to insulin induces insulin resistance through lysosomal and proteasomal degradation of the insulin receptor. Diabetologia 2017; 60: 2299–311.
-
6.
Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R, et al.. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab 2010; 12: 329–40.
-
7.
Zheng Y, Yamada H, Sakamoto K, Horita S, Kunimi M, Endo Y, et al.. Roles of insulin receptor substrates in insulin-induced stimulation of renal proximal bicarbonate absorption. J Am Soc Nephrol 2005; 16: 2288–95.
-
8.
Nakamura M, Satoh N, Suzuki M, Kume H, Homma Y, Seki G, et al.. Stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in type 2 diabetes with nephropathy. Biochem Biophys Res Commun 2015; 461: 154–8.
-
9.
Nakamura M, Yamazaki O, Shirai A, Horita S, Satoh N, Suzuki M, et al.. Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome. Kidney Int 2015; 87: 535–42.
-
10.
Soleimani M. Insulin resistance and hypertension: new insights. Kidney Int 2015; 87: 497–9.
-
11.
Horita S, Nakamura M, Suzuki M, Satoh N, Suzuki A, Seki G. Selective insulin resistance in the kidney. Biomed Res Int 2016; 2016: 5825170.
-
12.
Nishida H, Sohara E, Nomura N, Chiga M, Alessi DR, Rai T, et al.. Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. Hypertension 2012; 60: 981–90.
-
13.
Blazer-Yost BL, Liu X, Helman SI. Hormonal regulation of ENaCs: insulin and aldosterone. Am J Physiol 1998; 274: C1373–9.
-
14.
Féraille E, Rousselot M, Rajerison R, Favre H. Effect of insulin on Na+,K(+)-ATPase in rat collecting duct. J Physiol 1995; 488(Pt 1): 171–80.
-
15.
Ilatovskaya DV, Levchenko V, Brands MW, Pavlov TS, Staruschenko A. Cross-talk between insulin and IGF-1 receptors in the cortical collecting duct principal cells: implication for ENaC-mediated Na+ reabsorption. Am J Physiol Renal Physiol 2015; 308: F713–9.
-
16.
Loffing J, Korbmacher C. Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC). Pflugers Arch 2009; 458: 111–35.
-
17.
Fujii M, Amanso A, Abrahão TB, Lassègue B, Griendling KK. Polymerase delta-interacting protein 2 regulates collagen accumulation via activation of the Akt/mTOR pathway in vascular smooth muscle cells. J Mol Cell Cardiol 2016; 92: 21–9.
-
18.
Guo Q, Xu L, Li H, Sun H, Wu S, Zhou B. 4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via Akt/mTOR signaling. Biochem Biophys Res Commun 2017; 484: 529–35.
-
19.
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017; 168: 960–76.
-
20.
Abu-Remaileh M, Wyant GA, Kim C, Laqtom NN, Abbasi M, Chan SH, et al.. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 2017; 358: 807–13.
-
21.
Takayama K, Muto A, Kikuchi Y. Leucine/glutamine and v-ATPase/lysosomal acidification via mTORC1 activation are required for position-dependent regeneration. Sci Rep 2018; 8: 8278.
-
22.
McConnell M, Feng S, Chen W, Zhu G, Shen D, Ponnazhagan S, et al.. Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity. Oncotarget 2017; 8: 47675–90.
-
23.
Ardestani A, Lupse B, Kido Y, Leibowitz G, Maedler K. mTORC1 Signaling: A Double-Edged Sword in Diabetic β Cells. Cell Metab 2018; 27: 314–31.
-
24.
Satoh N, Yamada H, Yamazaki O, Suzuki M, Nakamura M, Suzuki A, et al.. A pure chloride channel mutant of CLC-5 causes Dent's disease via insufficient V-ATPase activation. Pflugers Arch 2016; 468: 1183–96.
-
25.
Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 2011; 334: 678–83.
-
26.
Kuwagata S, Kume S, Chin-Kanasaki M, Araki H, Araki S, Nakazawa J, et al.. MicroRNA148b-3p inhibits mTORC1-dependent apoptosis in diabetes by repressing TNFR2 in proximal tubular cells. Kidney Int 2016; 90: 1211–25.
-
27.
Lee-Kwon W, Kawano K, Choi JW, Kim JH, Donowitz M. Lysophosphatidic acid stimulates brush border Na+/H+ exchanger 3 (NHE3) activity by increasing its exocytosis by an NHE3 kinase A regulatory protein-dependent mechanism. J Biol Chem 2003; 278: 16494–501.
-
28.
Choi JY, Shah M, Lee MG, Schultheis PJ, Shull GE, Muallem S, et al.. Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule. J Clin Invest 2000; 105: 1141–6.
-
29.
Biner HL, Arpin-Bott MP, Loffing J, Wang X, Knepper M, Hebert SC, et al.. Human cortical distal nephron: distribution of electrolyte and water transport pathways. J Am Soc Nephrol 2002; 13: 836–47.
-
30.
Burg M, Grantham J, Abramow M, Orloff J. Preparation and study of fragments of single rabbit nephrons. Am J Physiol 1966; 210: 1293–8.
-
31.
Burg MB, Grantham J, Abramow M, Orloff J, Schafer JA. Preparation and study of fragments of single rabbit nephrons. J Am Soc Nephrol 1997; 8: 675–83.
-
32.
Schödel J, Klanke B, Weidemann A, Buchholz B, Bernhardt W, Bertog M, et al.. HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury. Am J Pathol 2009; 174: 1663–74.
-
33.
Mellman I, Fuchs R, Helenius A. Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 1986; 55: 663–700.
-
34.
Palokangas H, Metsikkö K, Väänänen K. Active vacuolar H+ATPase is required for both endocytic and exocytic processes during viral infection of BHK-21 cells. J Biol Chem 1994; 269: 17577–85.
-
35.
Artunc F, Schleicher E, Weigert C, Fritsche A, Stefan N, Häring HU. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol 2016; 12: 721–37.
-
36.
Bryniarski MA, Yee BM, Jaffri I, Chaves LD, Yu JA, Guan X, et al.. Increased megalin expression in early type 2 diabetes: role of insulin signaling pathways. Am J Physiol Renal Physiol 2018; 315: F1191–207.
-
37.
Gleixner EM, Canaud G, Hermle T, Guida MC, Kretz O, Helmstädter M, et al.. V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis. Cell Rep 2014; 8: 10–9.
-
38.
Alzamora R, Al-Bataineh MM, Liu W, Gong F, Li H, Thali RF, et al.. AMP-activated protein kinase regulates the vacuolar H+-ATPase via direct phosphorylation of the A subunit (ATP6V1A) in the kidney. Am J Physiol Renal Physiol 2013; 305: F943–56.
-
39.
Alzamora R, Thali RF, Gong F, Smolak C, Li H, Baty CJ, et al.. PKA regulates vacuolar H+-ATPase localization and activity via direct phosphorylation of the a subunit in kidney cells. J Biol Chem 2010; 285: 24676–85.
-
40.
Gong F, Alzamora R, Smolak C, Li H, Naveed S, Neumann D, et al.. Vacuolar H+-ATPase apical accumulation in kidney intercalated cells is regulated by PKA and AMP-activated protein kinase. Am J Physiol Renal Physiol 2010; 298: F1162–9.
-
41.
Al-bataineh MM, Gong F, Marciszyn AL, Myerburg MM, Pastor-Soler NM. Regulation of proximal tubule vacuolar H(+)-ATPase by PKA and AMP-activated protein kinase. Am J Physiol Renal Physiol 2014; 306: F981–95.
-
42.
Hallows KR, Alzamora R, Li H, Gong F, Smolak C, Neumann D, et al.. AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells. Am J Physiol Cell Physiol 2009; 296: C672–81.
-
43.
Guan X, Qian Y, Shen Y, Zhang L, Du Y, Dai H, et al.. Autophagy protects renal tubular cells against ischemia/reperfusion injury in a time-dependent manner. Cell Physiol Biochem 2015; 36: 285–98.
-
44.
Lin F. Autophagy in renal tubular injury and repair. Acta Physiol (Oxf) 2017; 220: 229–37.
-
45.
Lang F, Pearce D. Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway. Nephrol Dial Transplant 2016; 31: 200–5.
-
46.
Nakamura M, Tsukada H, Seki G, Satoh N, Mizuno T, Fujii W, et al.. Insulin promotes sodium transport but suppresses gluconeogenesis via distinct cellular pathways in human and rat renal proximal tubules. Kidney Int 2020; 97: 316–26.
Editor-in-Chief
László ROSIVALL (Semmelweis University, Budapest, Hungary)
Managing Editor
Anna BERHIDI (Semmelweis University, Budapest, Hungary)
Co-Editors
- Gábor SZÉNÁSI (Semmelweis University, Budapest, Hungary)
- Ákos KOLLER (Semmelweis University, Budapest, Hungary)
- Zsolt RADÁK (University of Physical Education, Budapest, Hungary)
- László LÉNÁRD (University of Pécs, Hungary)
- Zoltán UNGVÁRI (Semmelweis University, Budapest, Hungary)
Assistant Editors
- Gabriella DÖRNYEI (Semmelweis University, Budapest, Hungary)
- Zsuzsanna MIKLÓS (Semmelweis University, Budapest, Hungary)
- György NÁDASY (Semmelweis University, Budapest, Hungary)
Hungarian Editorial Board
- György BENEDEK (University of Szeged, Hungary)
- Zoltán BENYÓ (Semmelweis University, Budapest, Hungary)
- Mihály BOROS (University of Szeged, Hungary)
- László CSERNOCH (University of Debrecen, Hungary)
- Magdolna DANK (Semmelweis University, Budapest, Hungary)
- László DÉTÁRI (Eötvös Loránd University, Budapest, Hungary)
- Zoltán GIRICZ (Semmelweis University, Budapest, Hungary and Pharmahungary Group, Szeged, Hungary)
- Zoltán HANTOS (Semmelweis University, Budapest and University of Szeged, Hungary)
- Zoltán HEROLD (Semmelweis University, Budapest, Hungary)
- László HUNYADI (Semmelweis University, Budapest, Hungary)
- Gábor JANCSÓ (University of Pécs, Hungary)
- Zoltán KARÁDI (University of Pecs, Hungary)
- Miklós PALKOVITS (Semmelweis University, Budapest, Hungary)
- Gyula PAPP (University of Szeged, Hungary)
- Gábor PAVLIK (University of Physical Education, Budapest, Hungary)
- András SPÄT (Semmelweis University, Budapest, Hungary)
- Gyula SZABÓ (University of Szeged, Hungary)
- Zoltán SZELÉNYI (University of Pécs, Hungary)
- Lajos SZOLLÁR (Semmelweis University, Budapest, Hungary)
- József TOLDI (MTA-SZTE Neuroscience Research Group and University of Szeged, Hungary)
- Árpád TÓSAKI (University of Debrecen, Hungary)
International Editorial Board
- Dragan DJURIC (University of Belgrade, Serbia)
- Christopher H. FRY (University of Bristol, UK)
- Stephen E. GREENWALD (Blizard Institute, Barts and Queen Mary University of London, UK)
- Tibor HORTOBÁGYI (University of Groningen, Netherlands)
- George KUNOS (National Institutes of Health, Bethesda, USA)
- Massoud MAHMOUDIAN (Iran University of Medical Sciences, Tehran, Iran)
- Tadaaki MANO (Gifu University of Medical Science, Japan)
- Luis Gabriel NAVAR (Tulane University School of Medicine, New Orleans, USA)
- Hitoo NISHINO (Nagoya City University, Japan)
- Ole H. PETERSEN (Cardiff University, UK)
- Ulrich POHL (German Centre for Cardiovascular Research and Ludwig-Maximilians-University, Planegg, Germany)
- Andrej A. ROMANOVSKY (University of Arizona, USA)
- Anwar Ali SIDDIQUI (Aga Khan University, Karachi, Pakistan)
- Csaba SZABÓ (University of Fribourg, Switzerland)
- Eric VICAUT (Université de Paris, UMRS 942 INSERM, France)
Editorial Correspondence:
Physiology International
Semmelweis University
Faculty of Medicine, Institute of Translational Medicine
Nagyvárad tér 4, H-1089 Budapest, Hungary
Phone/Fax: +36-1-2100-100
E-mail: pi@semmelweis.hu
Indexing and Abstracting Services:
- Biological Abstracts
- BIOSIS Previews
- CAB Abstracts
- CABELLS Journalytics
- EMBASE/Excerpta Medica
- Global Health
- Index Copernicus
- Index Medicus
- Medline
- Referativnyi Zhurnal
- SCOPUS
- WoS - Science Citation Index Expanded
| 2023 | |
|---|---|
| Web of Science | |
| Journal Impact Factor | 2.2 |
| Rank by Impact Factor | Q3 (Physiology) |
| Journal Citation Indicator | 0.58 |
| Scopus | |
| CiteScore | 3.4 |
| CiteScore rank | Q2 (Physical Therapy, Sports Therapy and Rehabilitation) |
| SNIP | 0.508 |
| Scimago | |
| SJR index | 0.407 |
| SJR Q rank | Q2 |
| Physiology International | |
|---|---|
| Publication Model | Hybrid |
| Submission Fee | none |
| Article Processing Charge | 1100 EUR/article |
| Printed Color Illustrations | 40 EUR (or 10 000 HUF) + VAT / piece |
| Regional discounts on country of the funding agency | World Bank Lower-middle-income economies: 50% World Bank Low-income economies: 100% |
| Further Discounts | Editorial Board / Advisory Board members: 50% Corresponding authors, affiliated to an EISZ member institution subscribing to the journal package of Akadémiai Kiadó: 100% |
| Subscription fee 2025 | Online subsscription: 752 EUR / 828 USD Print + online subscription: 880 EUR / 968 USD |
| Subscription Information | Online subscribers are entitled access to all back issues published by Akadémiai Kiadó for each title for the duration of the subscription, as well as Online First content for the subscribed content. |
| Purchase per Title | Individual articles are sold on the displayed price. |
| Physiology International | |
|---|---|
| Language | English |
| Size | B5 |
| Year of Foundation |
2006 (1950) |
| Volumes per Year |
1 |
| Issues per Year |
4 |
| Founder | Magyar Tudományos Akadémia |
| Founder's Address |
H-1051 Budapest, Hungary, Széchenyi István tér 9. |
| Publisher | Akadémiai Kiadó |
| Publisher's Address |
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245. |
| Responsible Publisher |
Chief Executive Officer, Akadémiai Kiadó |
| ISSN | 2498-602X (Print) |
| ISSN | 2677-0164 (Online) |
Monthly Content Usage
| Abstract Views | Full Text Views | PDF Downloads | |
|---|---|---|---|
| Jul 2024 | 33 | 0 | 0 |
| Aug 2024 | 31 | 0 | 0 |
| Sep 2024 | 63 | 0 | 0 |
| Oct 2024 | 123 | 0 | 0 |
| Nov 2024 | 83 | 0 | 0 |
| Dec 2024 | 68 | 0 | 0 |
| Jan 2025 | 24 | 0 | 0 |
Copyright Akadémiai Kiadó AKJournals is the trademark of Akadémiai Kiadó's journal publishing business branch.