Neurotrophin-3 inhibits HCO absorption via a cAMP-dependent pathway in renal thick ascending limb.
Neurotrophins are expressed in the adult kidney, but their significance is unclear. We showed previously that nerve growth factor (NGF) inhibits HCO absorption in the rat medullary thick ascending limb (MTAL) via an extracellular signal-regulated kinase (ERK)-dependent pathway. Here we examined whether other neurotrophic factors affect MTAL HCO absorption. Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor had no effect. In contrast, neurotrophin-3 (NT-3, 0.7 nM) inhibited HCO absorption by 40% (half-maximal inhibition at approximately 0.4 nM). Inhibition by NT-3 was additive to inhibition by NGF. Inhibitors of ERK activation that block inhibition by NGF had no effect on inhibition by NT-3. In contrast, 8-bromo-cAMP or forskolin pretreatment blocked inhibition by NT-3 but not NGF. Inhibition by NT-3 was also blocked by the specific protein kinase A (PKA) inhibitor myristoylated PKI(14-22) amide and by vasopressin, which inhibits HCO absorption via cAMP. Inhibitors of phosphatidylinositol 3-kinase or protein kinase C did not affect NT-3-induced inhibition, but inhibition by NT-3 was eliminated by genistein, consistent with involvement of a receptor tyrosine kinase. These results demonstrate that NT-3 inhibits HCO absorption via a cAMP- and PKA-dependent pathway. NT-3 and NGF regulate MTAL ion transport through different signal transduction mechanisms. These studies establish a direct role for NT-3 in regulation of renal tubule transport and identify the MTAL as an important target for neurotrophins, which may be involved in the control of renal acid excretion.
Good
D W
DW
Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA. dgood@UTMB.edu
George
T
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D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000042:Absorption; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008138:Loop of Henle / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D020933:Neurotrophin 3 / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D009994:Osmolar Concentration; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012076:Renal Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
D015124:8-Bromo Cyclic Adenosine Monophosphate; D001127:Arginine Vasopressin; D001639:Bicarbonates; D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D019833:Genistein; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020928:Mitogen-Activated Protein Kinases; D020932:Nerve Growth Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D012076:Renal Agents; C495041:Gdnf protein, rat; C113580:U 0126