American journal of physiology. Renal physiology
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Am. J. Physiol. Renal Physiol. · Apr 2012
Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase.
The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-κB activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. ⋯ At 48 h after CLP, creatinine clearance was significantly higher in the CLP+EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-α activation, NF-κB activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-κB downregulation.
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Am. J. Physiol. Renal Physiol. · Apr 2012
mPGES-1 deletion potentiates urine concentrating capability after water deprivation.
PGE(2) plays an important role in the regulation of fluid metabolism chiefly via antagonizing vasopressin-induced osmotic permeability in the distal nephron, but its enzymatic sources remain uncertain. The present study was undertaken to investigate the potential role of microsomal PGE synthase (mPGES)-1 in the regulation of urine concentrating ability after water deprivation (WD). Following 24-h WD, wild-type (WT) mice exhibited a significant reduction in urine volume, accompanied by a significant elevation in urine osmolality compared with control groups. ⋯ Similar results were obtained by using immunohistochemistry. Paradoxically, plasma AVP response to WD seen in WT mice was absent in the KO mice. Taken together, these results suggest that mPGES-1-derived PGE(2) reduces urine concentrating ability through suppression of renal medullary expression of V(2) receptors and AQP2 but may enhance it by mediating the central AVP response.
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Am. J. Physiol. Renal Physiol. · Apr 2012
Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype.
The expression of the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by mineralocorticoids and, in turn, upregulates the renal epithelial Na(+) channel (ENaC). Total inactivation of Sgk1 has been associated with transient urinary Na(+) wasting with a low-Na(+) diet, while the aldosterone-mediated ENaC channel activation was unchanged in the collecting duct. Since Sgk1 is ubiquitously expressed, we aimed to study the role of renal Sgk1 and generated an inducible kidney-specific knockout (KO) mouse. ⋯ On a low-Na(+) diet, the Sgk1 KO mice were also hyperkaliuric and lost body weight. This phenotype was accompanied by a decrease in systolic and diastolic blood pressure. At the protein level, we observed a reduction in phosphorylation of the ubiquitin protein-ligase Nedd4-2 and a decrease in the expression of the Na(+)-Cl(-)-cotransporter (NCC) and to a lesser extent of ENaC.
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Am. J. Physiol. Renal Physiol. · Apr 2012
Isolated interstitial nodal spaces may facilitate preferential solute and fluid mixing in the rat renal inner medulla.
Recent anatomic findings indicate that in the upper inner medulla of the rodent kidney, tubules, and vessels are organized around clusters of collecting ducts (CDs). Within CD clusters, CDs and some of the ascending vasa recta (AVR) and ascending thin limbs (ATLs), when viewed in transverse sections, form interstitial nodal spaces, which are arrayed at structured intervals throughout the inner medulla. These spaces, or microdomains, are bordered on one side by a single CD, on the opposite side by one or more ATLs, and on the other two sides by AVR. ⋯ Fluid in all compartments contains Na(+), Cl(-), urea and, in the microdomain, negative fixed charges that represent macromolecules (e.g., hyaluronan) balanced by Na(+). Fluid entry into AVR is assumed to be driven by hydraulic and oncotic pressures. Model results suggest that the isolated microdomains facilitate solute and fluid mixing among the CDs, ATLs, and AVR, promote water withdrawal from CDs, and consequently may play an important role in generating the inner medullary osmotic gradient.
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Am. J. Physiol. Renal Physiol. · Mar 2012
Age-related decline in label-retaining tubular cells: implication for reduced regenerative capacity after injury in the aging kidney.
Recovery after acute kidney injury is impaired in the elderly, but the precise mechanism for such age-related incompetence remains unclear. By in vivo bromodeoxyuridine (BrdU) labeling, renal progenitor cells (label-retaining cells; LRCs) were identified in tubules of normal rat kidney and were shown to be the origin of proliferating cells after injury. In the present study, the involvement of LRCs in the age-related decline of tubular recovery after injury was examined. ⋯ When renal tubules isolated from rats treated with BrdU label were cocultured with human umbilical vein endothelial cells (HUVEC), the number of LRCs significantly increased compared with tubules cultured without HUVEC. These data suggest that the reduced capacity of tubular regeneration in the aging kidney is partly explained by the shortage of LRC reserves. The size of the LRC pool might be regulated by the surrounding peritubular capillary network.