Interaction between NO synthase and NADPH oxidase in control of sodium transport by the renal thick ascending limb during diabetes


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Abstract

AimDuring type 1 diabetes (T1D), the medullary thick ascending limb (mTAL) displays an NADPH oxidase-dependent increase in sodium transport, in concert with increased NO production by NO synthase 1 (NOS1) and NOS2. We hypothesized that NOS1- and/or NOS2-derived NO blunts T1D-induced activation of sodium transport in the mTAL.MethodsT1D was induced by streptozotocin injection (STZ rats); sham rats received vehicle. Three-to-four weeks later, mTAL were isolated from both groups for assay of nitrite and superoxide production, and O2 consumption in the absence or presence of various inhibitors.ResultsApocynin (NADPH oxidase inhibitor) normalized superoxide production and ouabain-sensitive O2 consumption and furosemide-sensitive O2 consumption by mTALs from STZ rats, without altering O2 consumption by mTALs from sham rats. Apocynin also unmasked a T1D-induced increase in nitrite production. NOS inhibition did not alter superoxide production in either group. In sham mTAL, total NOS inhibition, but not isoform-specific inhibition of NOS1 or NOS2, increased ouabain- and furosemide-sensitive O2 consumption, confirming a tonic inhibitory impact of NOS3 on sodium transport. In contrast, neither total nor isoform-specific NOS inhibition altered O2 consumption by STZ mTAL. Apocynin treatment of STZ mTAL unveiled the ability of isoform-specific NOS inhibition to significantly increase O2 consumption, without further increase in O2 consumption with total NOS inhibition.ConclusionUnder normal conditions, NOS3-derived NO inhibits sodium transport in the mTAL. T1D dismantles the impact of NOS-mediated inhibition of sodium transport as a result of NADPH oxidase-dependent NO scavenging. Inhibition of NADPH oxidase to preserve NO bioavailability reveals an inhibitory impact of NOS1- and NOS2-derived NO on sodium transport in the mTAL.

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