Acute growth hormone administration induces antidiuretic and antinatriuretic effects and increases phosphorylation of NKCC2.
Growth hormone (GH) has antidiuretic and antinatriuretic effects in rats and humans, but the molecular mechanisms responsible for these effects are unknown. The aim of this study was to investigate the mechanisms behind the acute renal effects of GH in rats. Female rats received rat (r)GH (2.8 mg/kg sc) or saline and were placed in metabolic cages for 5 h. Urinary excretion of electrolytes and urinary volume were reduced after rGH injection, while urine osmolality was increased. Creatinine and lithium clearance remained unchanged, suggesting that rGH increases reabsorption in segments distal to the proximal tubule. Total plasma insulin-like growth factor I (IGF-I) levels did not change, while cortical IGF-I mRNA abundance was increased. The relative abundance of total and Ser(256)-phosphorylated aquaporin 2 was found to be unchanged by immunoblotting, whereas a significant increase of Thr(96) and Thr(101)-phosphorylated NKCC2 (renal Na(+), K(+), 2Cl(-) cotransporter) was found in the inner stripe of outer medulla thick ascending limbs (mTAL). Additionally, an increased NKCC2 expression was observed in the cortical region. Immunohistochemistry confirmed these findings. The density of NKCC2 molecules in the apical membrane of mTAL cells appeared to be unchanged after rGH injection evaluated by immunoelectron microscopy. Basolateral addition of rGH or IGF-I to microperfused rat mTAL segments did not change transepithelial voltage. In conclusion, GH appears to exert its acute antinatriuretic and antidiuretic effects through indirect activation of NKCC2 in the mTAL.
Dimke
Henrik
H
The Water and Salt Research Centre, Institute of Anatomy, University of Aarhus, 8000 Aarhus C, Denmark.
Flyvbjerg
Allan
A
Bourgeois
Soline
S
Thomsen
Klaus
K
Frøkiaer
Jørgen
J
Houillier
Pascal
P
Nielsen
Søren
S
Frische
Sebastian
S
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D004231:Diuresis / Q000187:drug effects*; D005260:Female; D013006:Growth Hormone / Q000008:administration & dosage*; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000648:ultrastructure; D009318:Natriuresis / Q000187:drug effects*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D028021:Sodium-Potassium-Chloride Symporters / Q000276:immunology / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1
C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D007328:Insulin; C578714:SLC12A1 protein, human; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone