American journal of physiology. Renal physiology
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Am. J. Physiol. Renal Physiol. · May 2005
Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality.
In vitro studies suggest that endothelin-1 (ET-1) inhibits vasopressin (AVP)-stimulated water permeability in the collecting duct (CD). To evaluate the role of CD-derived ET-1 in regulating renal water metabolism, the ET-1 gene was selectively disrupted in the CD (CD ET-1 KO). During normal water intake, urinary osmolality (Uosm), plasma Na concentration, urine volume, and renal aquaporin-2 (AQP2) levels were unchanged, but plasma AVP concentration was reduced in CD ET-1 KO animals. ⋯ In response to continuous infusion of 1-desamino-8-D-arginine vasopressin, CD ET-1 KO mice had greater increases in Uosm, V2 and AQP2 mRNA, and phosphorylation of AQP2. CD suspensions from CD ET-1 KO mice had enhanced AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET-1 KO increases renal sensitivity to the urinary concentrating effects of AVP and suggest that ET-1 functions as a physiological autocrine regulator of AVP action in the CD.
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Am. J. Physiol. Renal Physiol. · Apr 2005
The role of NOS2 and NOS3 in renal protein and arginine metabolism during early endotoxemia in mice.
Previously, we observed an enhanced renal protein synthesis and increased de novo arginine production in the early response to endotoxemia in wild-type Swiss mice (Hallemeesch MM, Soeters PB, and Deutz NE. Am J Physiol Renal Physiol 282: F316-F323, 2002). To establish whether these changes are regulated by nitric oxide (NO) synthesized by NO synthase isoforms NOS2 and NOS3, we studied C57BL6/J wild-type (WT), NOS2-deficient (NOS2(-/-)), and NOS3-deficient (NOS3(-/-)) mice under baseline (unstimulated) and LPS-treated conditions. ⋯ Collectively, these data show that NOS2 is constitutively expressed in the kidney and remarkably functional as it affects renal blood flow and de novo arginine production under baseline conditions and is important for the increase in renal citrulline turnover during endotoxemia. NOS3, in contrast, appears less important for renal metabolism. The increase in renal protein turnover during endotoxemia does not depend on NOS2 or NOS3 activity.
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Am. J. Physiol. Renal Physiol. · Apr 2005
Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats.
Vasopressin and ANG II, which are known to play a major role in renal water and sodium reabsorption, are mainly coupled to the cAMP/PKA and phosphoinositide pathways, respectively. There is evidence for cross talk between these intracellular signaling pathways. We therefore hypothesized that vasopressin-induced water reabsorption could be attenuated by ANG II AT(1) receptor blockade in rats. ⋯ In conclusion, ANG II AT(1) receptor blockade in DDAVP-treated rats was associated with decreased urine concentration and decreased AQP2 and AQP1 expression. Moreover, FE(Na) was increased in parallel with decreased expression of NHE3, NCC, and Na-K-ATPase. These results suggest that ANG II AT(1) receptor activation plays a significant role in regulating aquaporin and sodium transporter expression and modulating urine concentration in vivo.
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Am. J. Physiol. Renal Physiol. · Apr 2005
Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria.
The use of LiCl in clinical psychiatry is routinely complicated by overt nephrogenic diabetes insipidus (NDI), the mechanism of which is incompletely understood. In vitro studies indicate that lithium can induce renal medullary interstitial cell cyclooxygenase 2 (COX2) protein expression via inhibition of glycogen synthase kinase-3beta (GSK-3beta). Both COX1 and COX2 are expressed in the kidney. ⋯ Lithium also decreased renal medullary GSK-3beta activity, and this was temporally related to increased COX2 expression in the kidney from lithium-treated mice, consistent with a tonic in vivo suppression of COX2 expression by GSK-3 activity. In conclusion, these findings temporally link decreased GSK-3 activity to enhanced renal COX2 expression and COX2-derived urine PGE(2) excretion. Suppression of COX2-derived PGE(2) blunts lithium-associated polyuria.
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Am. J. Physiol. Renal Physiol. · Mar 2005
Elimination of rat spinal neurons expressing neurokinin 1 receptors reduces bladder overactivity and spinal c-fos expression induced by bladder irritation.
Substance P (SP) binding to neurokinin 1 receptors (NK1R) in the spinal cord reportedly plays an important role in the micturition reflex as well as in nociceptive responses. We therefore investigated the effect of ablation of NK1R-expressing neurons in the spinal cord using saporin, a ribosome-inactivating protein, conjugated with [Sar9, Met (O2)11]SP, a specific ligand of NK1R (SSP-saporin), on the micturition reflex in rats. In female Sprague-Dawley rats, SSP-saporin (1.0 or 1.5 microM) or saporin (1.5 microM) only was injected through an intrathecal catheter implanted at the L6-S1 level of the spinal cord. ⋯ SSP-saporin treatment also decreased c-fos expression in the dorsal horn of the spinal cord induced by instillation of capsaicin into the bladder. These data indicate that NK1R-expressing neurons in the superficial layer of the dorsal horn play an important role in transmission of nociceptive afferent information from the bladder to induce bladder overactivity and spinal c-fos expression elicited by bladder irritation. Toxin-induced damage of NK1R-expressing neurons in the lumbosacral spinal cord may provide an effective modality for treating overactivity and/or nociceptive responses in the bladder without affecting normal micturition.