Dysregulation renaler Salztransporter in mit Gentamicin behandelten Ratten

Ziel dieser Arbeit war es die zugrunde liegenden molekularen Mechanismen für den renalen Verlust von Na+, K+, Ca2+ und Mg2+ in mit Gentamicin (GM) behandelten Ratten zu untersuchen. In zwei Tiermodellen injizierten wir männlichen Wistar Ratten GM (40 bzw. 80 mg/kg/d über 7 Tage; GM-40 bzw. GM-80). W...

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Bibliographic Details
Main Author: Sassen, Martin Christian
Contributors: Klaus, Günter (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2012
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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 80mg/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 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 (40mg/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.