Rab-GAP TBC1D4 (AS160) is dispensable for the renal control of sodium and water homeostasis but regulates GLUT4 in mouse kidney.
The Rab GTPase-activating protein TBC1D4 (AS160) controls trafficking of the glucose transporter GLUT4 in adipocytes and skeletal muscle cells. TBC1D4 is also highly abundant in the renal distal tubule, although its role in this tubule is so far unknown. In vitro studies suggest that it is involved in the regulation of renal transporters and channels such as the epithelial sodium channel (ENaC), aquaporin-2 (AQP2), and the Na+-K+-ATPase. To assess the physiological role of TBC1D4 in the kidney, wild-type (TBC1D4+/+) and TBC1D4-deficient (TBC1D4-/-) mice were studied. Unexpectedly, neither under standard nor under challenging conditions (low Na+/high K+, water restriction) did TBC1D4-/- mice show any difference in urinary Na+ and K+ excretion, urine osmolarity, plasma ion and aldosterone levels, and blood pressure compared with TBC1D4+/+ mice. Also, immunoblotting did not reveal any change in the abundance of major renal sodium- and water-transporting proteins [Na-K-2Cl cotransporter (NKCC2) NKCC2, NaCl cotransporter (NCC), ENaC, AQP2, and the Na+-K+-ATPase]. However, the abundance of GLUT4, which colocalizes with TBC1D4 along the distal nephron of TBC1D4+/+ mice, was lower in whole kidney lysates of TBC1D4-/- mice than in TBC1D4+/+ mice. Likewise, primary thick ascending limb (TAL) cells isolated from TBC1D4-/- mice showed an increased basal glucose uptake and an abrogated insulin response compared with TAL cells from TBC1D4+/+ mice. Thus, TBC1D4 is dispensable for the regulation of renal Na+ and water transport, but may play a role for GLUT4-mediated basolateral glucose uptake in distal tubules. The latter may contribute to the known anaerobic glycolytic capacity of distal tubules during renal ischemia.
Institute of Anatomy, University of Zurich, Zurich, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland;
Marianna
M
Di Chiara
Institute of Physiology, University of Zurich, Zurich, Switzerland;
Bob
B
Glaudemans
Institute of Anatomy, University of Zurich, Zurich, Switzerland;
Dominique
D
Loffing-Cueni
Division of Molecular and Systems Toxicology, Pharmacenter, University of Basel, Basel, Switzerland; National Center of Competence in Research "Kidney.CH," Switzerland; and.
Alex
A
Odermatt
German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University and German Center for Diabetes Research, Düsseldorf, Germany.
Hadi
H
Al-Hasani
Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Institute of Physiology, University of Zurich, Zurich, Switzerland; National Center of Competence in Research "Kidney.CH," Switzerland; and.
Olivier
O
Devuyst
Institute of Anatomy, University of Zurich, Zurich, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland; National Center of Competence in Research "Kidney.CH," Switzerland; and.
Nourdine
N
Faresse
Institute of Anatomy, University of Zurich, Zurich, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland; National Center of Competence in Research "Kidney.CH," Switzerland; and johannes.loffing@anatom.uzh.ch.
Johannes
J
Loffing
D000818:Animals; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D008138:Loop of Henle / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D010320:Parvalbumins / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012084:Renin-Angiotensin System; D012964:Sodium / Q000378:metabolism*; D014882:Water-Electrolyte Balance
D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D010320:Parvalbumins; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D012964:Sodium; D005947:Glucose
distal tubule; glucose; hypertension; ion transport