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Dysregulation of renal sodium transporters in gentamicin-treated rats

Kidney International, ISSN: 0085-2538, Vol: 70, Issue: 6, Page: 1026-1037
2006
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Article Description

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, α -, β - and γ -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 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 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.

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