TY - JOUR
T1 - Dysregulation of renal sodium transporters in gentamicin-treated rats
AU - Sassen, M. C.
AU - Kim, S. W.
AU - Kwon, T. H.
AU - Knepper, M. A.
AU - Miller, R. T.
AU - Frøkiær, J.
AU - Nielsen, S.
N1 - Funding Information:
We thank Inger Merete Paulsen, Lotte Vallentin Holbech, Ida Maria Jalk, Gitte Kall, Helle Høyer, Zhila Nikrozi, Mette Vistisen, and Dorte Wulff for expert technical assistance. Martin C Sassen was supported by an EMBO short-term fellowship. The Water and Salt Research Center at the University of Aarhus is established and supported by the Danish National Research Foundation (Danmakrs Grundforskningsfond). The support for this study was provided by the WIRED program (Nordic Council and the Nordic Centre of Excellence Program in Molecular Medicine), Karen Elise Jensen Foundation, Human Frontier Science Program, the European Commission (QRLT 2000 00778 and QRLT 2000 00987), the Regional Technology Innovation Program of the MOCIE (RTI04-01-01, T-H Kwon), and the intramural budget of the National Heart, Lung, and Blood Institute, NIH.
PY - 2006/9
Y1 - 2006/9
N2 - We aimed to investigate the molecular mechanisms underlying the renal wasting of Na+, K+, Ca2+, and Mg2+ 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, α-, β- and γ-ENaC, and CaSR was examined in the kidney by immunoblotting and immunohistochemistry. Urinary fractional excretion of Na+, K+, Ca2+, and Mg2+ 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 α-, β-, and γ-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 Mg2+ and Ca2+, 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.
AB - We aimed to investigate the molecular mechanisms underlying the renal wasting of Na+, K+, Ca2+, and Mg2+ 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, α-, β- and γ-ENaC, and CaSR was examined in the kidney by immunoblotting and immunohistochemistry. Urinary fractional excretion of Na+, K+, Ca2+, and Mg2+ 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 α-, β-, and γ-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 Mg2+ and Ca2+, 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.
KW - Calcium-sensing receptor
KW - Concentrating defect
KW - NKCC2
KW - Nephrotoxicity
KW - Renal magnesium wasting
KW - Sodium transport
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U2 - 10.1038/sj.ki.5001654
DO - 10.1038/sj.ki.5001654
M3 - Article
C2 - 16850027
AN - SCOPUS:33748421761
SN - 0085-2538
VL - 70
SP - 1026
EP - 1037
JO - Kidney international
JF - Kidney international
IS - 6
ER -