title: Dysregulation of renal sodium transporters in gentamicin-treated rats.
abstract: We aimed to investigate the molecular mechanisms underlying the renal wasting of Na(+), K(+), Ca(2+), and Mg(2+) in gentamicin (GM)-treated rats. Male Wistar rats were injected with GM (40 or 80 mg/kg/day for 7 days, respectively; GM-40 or GM-80). The expression of NHE3, Na-K-ATPase, NKCC2, ROMK, NCC, alpha-, beta- and gamma-ENaC, and CaSR was examined in the kidney by immunoblotting and immunohistochemistry. Urinary fractional excretion of Na(+), K(+), Ca(2+), and Mg(2+) was increased and urinary concentration was decreased in both GM-40 and GM-80 rats. In cortex and outer stripe of outer medulla (cortex) in GM-80 rats, the expression of NHE3, Na-K-ATPase, and NKCC2 was decreased; NCC expression was unchanged; and CaSR was upregulated compared to controls. In the inner stripe of outer medulla (ISOM) in GM-80 rats, NKCC2 and Na-K-ATPase expression was decreased, whereas CaSR was upregulated, and NHE3 and ROMK expression remained unchanged. In GM-40 rats, NKCC2 expression was decreased in the cortex and ISOM, whereas NHE3, Na-K-ATPase, CaSR, ROMK, and NCC abundance was unchanged in both cortex and ISOM. Immunoperoxidase labeling confirmed decreased expression of NKCC2 in the thick ascending limb (TAL) in both GM-80- and GM-40-treated rats. Immunoblotting and immunohistochemical analysis revealed increased expression of alpha-, beta-, and gamma-ENaC in cortex in GM-80 rats, but not in GM-40 rats. These findings suggest that the decrease in NKCC2 in TAL seen in response to low-dose (40 mg/kg/day) gentamicin treatment may play an essential role for the increased urinary excretion of Mg(2+) and Ca(2+), and play a significant role for the development of the urinary concentrating defect, and increased urinary excretion of Na(+) and K(+). At high-dose gentamicin, both proximal and TAL sodium transporter downregulation is likely to contribute to this.
authors.affiliation: The Water and Salt Research Center, University of Aarhus, Aarhus C, Denmark.
authors.forename: M C
authors.initials: MC
authors.lastname: Sassen
authors.forename: S W
authors.initials: SW
authors.lastname: Kim
authors.forename: T-H
authors.initials: TH
authors.lastname: Kwon
authors.forename: M A
authors.initials: MA
authors.lastname: Knepper
authors.forename: R T
authors.initials: RT
authors.lastname: Miller
authors.forename: J
authors.initials: J
authors.lastname: Frøkiaer
authors.forename: S
authors.initials: S
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005839:Gentamicins / Q000493:pharmacokinetics / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D008274:Magnesium / Q000652:urine; D008297:Male; D011188:Potassium / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D012964:Sodium / Q000378:metabolism* / Q000652:urine; D015222:Sodium Channels / Q000187:drug effects*; D049992:Sodium Chloride Symporters / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D044169:Receptors, Calcium-Sensing; D015222:Sodium Channels; D049992:Sodium Chloride Symporters; D027982:Sodium-Bicarbonate Symporters; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; C473605:extracellular calcium cation-sensing receptor, rat; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium; D011188:Potassium; D002118:Calcium