American journal of physiology. Renal physiology
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Am. J. Physiol. Renal Physiol. · Apr 2011
Small interfering RNA targeting IKKβ prevents renal ischemia-reperfusion injury in rats.
The transcription factor NF-κB has been found critical to the pathogenesis of renal ischemia-reperfusion injury, which is a major cause of acute kidney injury (AKI). Activation of NF-κB is dependent upon the activation of the specific inhibitory κB kinase (IKK) subunit IKKβ. Here, we investigate whether small interfering RNA (siRNA) targeting IKKβ protects rats from renal ischemia- reperfusion injury in vivo. ⋯ A local injection of IKKβ siRNA resulted in inhibition of renal IKKβ gene expression, NF-κB/DNA binding activity, and expression of NGAL and IL-18. Rats pretreated with IKKβ siRNA had significantly less blood urea nitrogen and serum creatinine levels and less renal tubular damage scores. Consequently, our data confirm that targeted silencing of IKKβ using siRNA substantially diminishes kidney injury and inflammation following ischemia-reperfusion.
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Am. J. Physiol. Renal Physiol. · Mar 2011
Renal cortical albumin gene induction and urinary albumin excretion in response to acute kidney injury.
This study evaluated the potential utility of albuminuria as a "biomarker" of acute kidney injury (AKI) and tested whether AKI induces renal expression of the normally silent albumin gene. Urine albumin concentrations were measured in mice with five different AKI models (maleate, ischemia-reperfusion, rhabdomyolysis, endotoxemia, ureteral obstruction). Albumin gene induction in renal cortex, and in antimycin A-injured cultured proximal tubular cells, was assessed (mRNA levels; RNA polymerase II binding to the albumin gene). ⋯ A correlate in patients was increased urinary α-fetoprotein excretion. We conclude that AKI can unmask, in the kidney, the normally silent renal albumin and α-fetoprotein genes. In addition, the urinary protein data independently indicate that albuminuria, and perhaps α-fetoprotein, have substantial utility as biomarkers of acute tubular injury.
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Am. J. Physiol. Renal Physiol. · Mar 2011
Cyclophosphamide induces NR2B phosphorylation-dependent facilitation on spinal reflex potentiation.
It is well-established that cyclophosphamide (CYP) can sensitize the pelvic afferent nerve arising from the urinary bladder and therefore induce suprapubic pain. To test the possibility that CYP might mediate the development of visceral hypereflexia/hyperalgesia by facilitating spinal activity-dependent neural plasticity, we compared the pelvic-urethra reflex activity and spinal N-methyl-d-aspartate receptor NR2B subunit (NR2B) phosphorylation in rats treated with vehicle solution and CYP. ⋯ When compared with the untreated group, the treatment with small-interfering RNA of NR2B, which decreased the expression of NR2B expression, abolished CYP-dependent reflex facilitation and spinal NR2B phosphorylation. These results suggested that CYP might facilitate spinal reflex potentiation mediated by N-methyl-d-aspartate receptors and participate in the development of visceral hypereflexia/hyperalgesia through nitric oxide- and Cdk5-dependent NR2B phosphorylation at the lumbosacral dorsal horn.
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Am. J. Physiol. Renal Physiol. · Feb 2011
EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B.
Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in pain-related neural plasticity at the spinal cord level have been identified. To test whether Src-family tyrosine kinase-dependent glutamatergic N-methyl-d-aspartate receptor NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate pelvic-urethra reflex potentiation, we recorded external urethra sphincter electromyogram reflex activity and analyzed protein expression in the lumbosacral (L(6)-S(2)) dorsal horn in response to intrathecal ephrinB2 injections. ⋯ Pretreatment with PP2 (50 μM, 10 μl it), an Src-family kinase antagonist, reversed the reflex potentiation, as well as Src kinase and NR2B phosphorylation. Together, these results suggest the ephrinB2-dependent EphBR activation, which subsequently provokes Src kinase-mediated N-methyl-d-aspartate receptor NR2B phosphorylation in the lumbosacral dorsal horn, is crucial for the induction of spinal reflex potentiation contributing to the development of visceral pain and/or hyperalgesia in the pelvic area.
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Am. J. Physiol. Renal Physiol. · Feb 2011
A mathematical model of the urine concentrating mechanism in the rat renal medulla. I. Formulation and base-case results.
A new, region-based mathematical model of the urine concentrating mechanism of the rat renal medulla was used to investigate the significance of transport and structural properties revealed in anatomic studies. The model simulates preferential interactions among tubules and vessels by representing concentric regions that are centered on a vascular bundle in the outer medulla (OM) and on a collecting duct cluster in the inner medulla (IM). Particularly noteworthy features of this model include highly urea-permeable and water-impermeable segments of the long descending limbs and highly urea-permeable ascending thin limbs. ⋯ Model simulations predict that the interstitial NaCl and urea concentrations in adjoining regions differ substantially in the OM but not in the IM. In the OM, active NaCl transport from thick ascending limbs, at rates inferred from the physiological literature, resulted in a concentrating effect such that the intratubular fluid osmolality of the collecting duct increases ~2.5 times along the OM. As a result of the separation of urea from NaCl and the subsequent mixing of that urea and NaCl in the interstitium and vasculature of the IM, collecting duct fluid osmolality further increases by a factor of ~1.55 along the IM.