American journal of physiology. Renal physiology
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Am. J. Physiol. Renal Physiol. · Apr 2013
Inhibitory phosphorylation of GSK-3β by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP).
High NaCl activates the transcription factor nuclear factor of activated T cells 5 (NFAT5), leading to increased transcription of osmoprotective target genes. Kinases PKA, PI3K, AKT1, and p38α were known to contribute to the high NaCl-induced increase of NFAT5 activity. We now identify another kinase, GSK-3β. siRNA-mediated knock-down of GSK-3β increases NFAT5 transcriptional and transactivating activities without affecting high NaCl-induced nuclear localization of NFAT5 or NFAT5 protein expression. ⋯ Overexpression of PKA catalytic subunit α or of catalytically active AKT1 reduces inhibition of NFAT5 by GSK-3β, but overexpression of p38α together with its catalytically active upstream kinase, MKK6, does not. Thus, GSK-3β normally inhibits NFAT5 by suppressing its transactivating activity. When activated by high NaCl, PKA, PI3K, and AKT1, but not p38α, increase phosphorylation of GSK-3β-S9, which reduces the inhibitory effect of GSK-3β on NFAT5, and thus contributes to activation of NFAT5.
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Am. J. Physiol. Renal Physiol. · Mar 2013
Sensory renal innervation: a kidney-specific firing activity due to a unique expression pattern of voltage-gated sodium channels?
Sensory neurons with afferent axons from the kidney are extraordinary in their response to electrical stimulation. More than 50% exhibit a tonic firing pattern, i.e., sustained action potential firing throughout depolarizing, pointing to an increased excitability, whereas nonrenal neurons show mainly a phasic response, i.e., less than five action potentials. Here we investigated whether these peculiar firing characteristics of renal afferent neurons are due to differences in the expression of voltage-gated sodium channels (Navs). ⋯ Interestingly, mRNA expression of TTX-resistant sodium channels was significantly increased in renal, predominantly tonic, DRG neurons. Hence, under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings support that this is due to an increased expression and activation of TTX-resistant Navs.
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Am. J. Physiol. Renal Physiol. · Feb 2013
Axial compartmentation of descending and ascending thin limbs of Henle's loops.
In the inner medulla, radial organization of nephrons and blood vessels around collecting duct (CD) clusters leads to two lateral interstitial regions and preferential intersegmental fluid and solute flows. As the descending (DTLs) and ascending thin limbs (ATLs) pass through these regions, their transepithelial fluid and solute flows are influenced by variable transepithelial solute gradients and structure-to-structure interactions. The goal of this study was to quantify structure-to-structure interactions, so as to better understand compartmentation and flows of transepithelial water, NaCl, and urea and generation of the axial osmotic gradient. ⋯ These relationships occur regardless of loop length. Finally, we show that ascending vasa recta separate intercluster AQP1-positive DTLs from descending vasa recta, thereby minimizing dilution of gradients that drive solute secretion. We hypothesize that DTLs and ATLs enter and exit CD clusters in an orchestrated fashion that is important for generation of the corticopapillary solute gradient by minimizing NaCl and urea loss.
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PGE(2) is a natriuretic factor whose production is elevated after water deprivation (WD) but its role in dehydration natriuresis is not well-defined. The goal of the present study was to investigate the role of microsomal prostaglandin E synthase-1 (mPGES-1) in dehydration natriuresis. After 24-h WD, wild-type (WT) mice exhibited a significant increase in 24-h urinary Na(+) excretion accompanied with normal plasma Na(+) concentration and osmolality. ⋯ By quantitative RT-PCR, WD increased the endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS expressions in the renal medulla of WT mice by 3.9-, 1.48-, and 2.6-fold, respectively, all of which were significantly blocked in mPGES-1 KO mice. The regulation of eNOS expression was further confirmed by immunoblotting. Taken together, our results suggest that mPGES-1-derived PGE(2) contributes to dehydration natriuresis likely via NO/cGMP.
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Am. J. Physiol. Renal Physiol. · Jan 2013
Upregulation of soluble epoxide hydrolase in proximal tubular cells mediated proteinuria-induced renal damage.
Epoxyeicosatrienoic acids, hydrolyzed by soluble epoxide hydrolase (sEH), have multiple biological functions, including the regulation of vascular tone, renal tubular transport, and being anti-inflammatory. Inhibitors of sEH have been demonstrated to be antihypertensive and renal protective. To elucidate the role of sEH in glomerulonephritis, we first determined the expression of sEH in human kidney by examining biopsies from 153 patients with a variety of glomerulonephritis, including minimal-change, membranous, and IgA nephropathy. ⋯ These effects were attenuated by administration of a potent sEH inhibitor and mimicked with adenovirus-mediated sEH overexpression. In adriamycin-induced nephropathic mice, sEH inhibitor did not ameliorate proteinuria or level of serum albumin but reduced the long-term elevated serum creatinine level, interstitial inflammation, fibrosis, and α-SMA expression. Thus upregulation of sEH in proximal tubular cells in chronic proteinuric kidney diseases may mediate proteinuria-induced renal damage; sEH inhibition by increasing renal eicosanoid levels could prevent the progression of chronic proteinuric kidney diseases.