American journal of physiology. Renal physiology
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Am. J. Physiol. Renal Physiol. · Aug 2005
A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis.
Sepsis is a leading cause of multiorgan dysfunction and death in hospitalized patients. Dysregulated inflammatory processes and apoptosis contribute to the pathogenesis of sepsis-induced organ dysfunction and death. A(1) adenosine receptor (A(1)AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. ⋯ The renal corticomedullary junction from A(1) knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A(1) wild-type littermate controls. No difference in renal tubular apoptosis was detected between A(1) knockout and A(1) wild-type mice. We conclude that endogenous A(1)AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
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Am. J. Physiol. Renal Physiol. · Aug 2005
COX-2 inhibition prevents downregulation of key renal water and sodium transport proteins in response to bilateral ureteral obstruction.
Bilateral ureteral obstruction (BUO) is associated with marked changes in the expression of renal aquaporins (AQPs) and sodium transport proteins. To examine the role of prostaglandin in this response, we investigated whether 24-h BUO changed the expression of cyclooxygenases (COX-1 and -2) in the kidney and tested the effect of the selective COX-2 inhibitor parecoxib (5 mg.kg(-1).day(-1) via osmotic minipumps) on AQPs and sodium transport. Sham and BUO kidneys were analyzed by semiquantitative immunoblotting, and a subset of kidneys was perfusion fixed for immunocytochemistry. ⋯ Parecoxib had no significant effect on the Na-K-ATPase alpha(1)-subunit, type II Na-P(i) cotransporter, or AQP3. In conclusion, acute BUO leads to marked upregulation of COX-2 in inner medulla and selective COX-2 inhibition prevents dysregulation of AQP2, BSC-1, and NHE3 in response to BUO. These data indicate that COX-2 may be an important factor contributing to the impaired renal water and sodium handling in response to BUO.
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Am. J. Physiol. Renal Physiol. · Jul 2005
Comparative StudyAltered expression profile of transporters in the inner medullary collecting duct of aquaporin-1 knockout mice.
Aquaporin-1 is the major protein responsible for transport of water across the epithelia of the proximal tubule and thin descending limbs. Rapid water efflux across the thin descending limb is required for the normal function of the countercurrent multiplier mechanism. Therefore, urinary concentrating capacity is severely impaired in aquaporin-1 knockout (AQP1 -/-) mice. ⋯ As in the AQP1 knockout mice, ClC-nK1 (-/-) mice showed decreased expression of UT-A1 and increased expression of beta-ENaC and gamma-ENaC vs. WT controls. In conclusion, the expression profile of IMCD transporters is markedly altered in AQP1 -/- mice and this manifestation is related to the associated concentrating defect.
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Am. J. Physiol. Renal Physiol. · Jun 2005
Comparative StudyP2Y2 receptor mRNA and protein expression is altered in inner medullas of hydrated and dehydrated rats: relevance to AVP-independent regulation of IMCD function.
Arginine vasopressin (AVP), acting through a cAMP second messenger system, regulates osmotic water permeability (Pf) of the collecting duct. In the collecting duct, the activities of cAMP and phosphonositides (PI) are mutually inhibitory. The P2Y2 receptor (P2Y2-R) is a G protein-coupled extracellular nucleotide receptor associated with PI signaling pathway. ⋯ Sequential hydration and dehydration experiments also revealed that the regulated expression profiles of P2Y2-R mRNA and protein are discordant. Conversely, the expression of V2-R mRNA remained unaltered during hydration and dehydration. Because virtually all renal cells release ATP in a regulated fashion, the observed alterations in P2Y2-R expression in the inner medulla in hydrated and dehydrated states may constitute a novel mechanism of purinergic modulation of IMCD function.
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Am. J. Physiol. Renal Physiol. · May 2005
Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice.
Caspase-1-deficient (-/-) mice are protected against sepsis-induced hypotension and mortality. We investigated the role of caspase-1 and its associated cytokines in a nonhypotensive model of endotoxemic acute renal failure (ARF). Mice were injected intraperitoneally with 2.5 mg of LPS that induces endotoxemic ARF. ⋯ In summary, caspase-1 -/- mice are functionally protected against endotoxemic ARF. Neutralization of IL-1beta and IL-18 is not functionally protective. The role of the intracellular proinflammatory cytokine IL-1alpha in endotoxemic ARF merits further study.