Patients with acute kidney injury (AKI) frequently suffer from extra-renal complications including hepatic dysfunction and systemic inflammation. We aimed to determine the mechanisms of AKI induced hepatic dysfunction and systemic inflammation. Mice subjected to AKI [renal ischemia reperfusion (IR) or nephrectomy] rapidly developed acute hepatic dysfunction and suffered significantly worse hepatic IR injury. After AKI, rapid peri-portal hepatocyte necrosis, vacuolization, neutrophil infiltration and pro-inflammatory mRNA upregulation were observed suggesting an intestinal source of hepatic injury. Small intestine histology after AKI demonstrated profound villous lacteal capillary endothelial apoptosis, disruption of vascular permeability and epithelial necrosis. After ischemic or non-ischemic AKI, plasma TNF-α, IL-17A and IL-6 increased significantly. Small intestine appears to be the source of IL-17A as IL-17A levels were higher in the portal circulation and small intestine compared to the levels measured from the systemic circulation and liver. Wild type mice treated with neutralizing antibodies against TNF-α, IL-17A or IL-6 or mice deficient in TNF-α, IL-17A, IL-17A receptor or IL-6 were protected against hepatic and small intestine injury due to ischemic or non-ischemic AKI. For the first time, we implicate the increased release of IL-17A from small intestine together with induction of TNF-α and IL-6 as a cause of small intestine and liver injury after ischemic or non-ischemic AKI. Modulation of the inflammatory response and cytokine release in the small intestine after AKI may have important therapeutic implications in reducing complications arising from AKI.

Utilizing a murine model, we tested the hypothesis that ␣ 2-adrenergic receptor agonists (clonidine and dexmedetomidine) protect against RCN induced with iohexol (a nonionic low-osmolar radiocontrast). C57BL/6 mice were pretreated with saline, clonidine, or dexmedetomidine before induction of RCN. Some mice were pretreated with yohimbine (a selective ␣ 2-receptor antagonist) before saline, clonidine, or dexmedetomidine administration. ␣2-Agonist-treated mice had reduced plasma creatinine, renal tubular necrosis, renal apoptosis, and renal cortical proximal tubule vacuolization 24 h after iohexol injection. Yohimbine reversed the protective effects of clonidine and dexmedetomidine pretreatment. Injection of iohexol resulted in a rapid (ϳ90 min) fall of renal outer medullary blood flow. Clonidine and dexmedetomidine pretreatment significantly attenuated this perfusion decrease without changing systemic blood pressure. To determine whether proximal tubular ␣ 2-adrenergic receptors mediate the cytoprotective effects, we treated cultured human proximal tubule (HK-2) cells and rat pulmonary microvascular endothelial cells with iohexol after vehicle, clonidine, or dexmedetomidine pretreatment. Iohexol caused a direct dose-dependent reduction of HK-2 and rat pulmonary microvascular endothelial cell viability, but ␣ 2-agonists failed to preserve the viability of both cell types. We conclude that ␣ 2-adrenergic receptor agonists protect mice against RCN by preserving outer medullary renal blood flow. As ␣2-agonists are widely utilized during the perioperative period, our findings may have significant clinical relevance to improving outcomes following radiocontrast exposure.acute renal failure; iohexol; clonidine; dexmedetomidine; yohimbine; HK-2 cells; medullary ischemia ARTERIOGRAPHY, ANGIOCARDIOGRAPHY, and contrast-enhanced CT scans account for Ͼ3,000,000 iodinated radiocontrast exposures each year in the United States (15). Renal dysfunction secondary to radiocontrast administration remains prevalent and debilitating (3). Radiocontrast nephropathy (RCN) remains the third most common cause of inpatient acute renal failure, behind ischemia-reperfusion injury and nephrotoxic medication administration (23). The diagnosis of RCN confers a 5.5-fold increase in hospital mortality (18,29), may necessitate hemodialysis (7), and is associated with an increased length of hospital stay and incidence of myocardial infarction (25).Although the pathogenesis of RCN remains incompletely understood, tubular hypoxic injury, due to a reduction of renal medullary blood flow, and direct tubular cytotoxicity play a substantial role (8,12,31). The risk of developing nephropathy after radiocontrast exposure may be as high as 50%, depending on numerous risk factors (21). Preexisting renal dysfunction and dehydration are the most predictive contributors to RCN, whereas volume of contrast exposure, contrast osmolality, congestive heart failure, diabetes, anemia, and advanced age also increase risk (2, 3). Despite the exploration of numerous proph...

Genetic deletion of the adenosine A1 receptor (A1AR) increased renal injury following ischemia-reperfusion injury suggesting that receptor activation is protective in vivo. Here we tested this hypothesis by expressing the human-A1AR in A1AR knockout mice. Renal ischemia-reperfusion was induced in knockout mice 2 days after intrarenal injection of saline or a lentivirus encoding enhanced green fluorescent protein (EGFP) or EGFP-human-A1AR. We found that the latter procedure induced a robust expression of the reporter protein in the kidneys of knockout mice. Mice with kidney-specific human-A1AR reconstitution had significantly lower plasma creatinine, tubular necrosis, apoptosis, and tubular inflammation as evidenced by decreased leukocyte infiltration, pro-inflammatory cytokine, and intercellular adhesion molecule-1 expression in the kidney following injury compared to mice injected with saline or the control lentivirus. Additionally, there were marked disruptions of the proximal tubule epithelial filamentous (F)-actin cytoskeleton in both sets of control mice upon renal injury, whereas the reconstituted mice had better preservation of the renal tubule actin cytoskeleton, which co-localized with the human-A1ARs. Consistent with reduced renal injury, there was a significant increase in heat shock protein-27 expression, also co-localizing with the preserved F-actin cytoskeleton. Our findings suggest that selective expression of cytoprotective A1ARs in the kidney can attenuate renal injury.

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Liver failure due to ischemia and reperfusion (IR) and subsequent acute kidney injury are significant clinical problems. We showed previously that liver IR selectively reduced plasma sphinganine-1-phosphate levels without affecting sphingosine 1-phosphate (S1P) levels. Furthermore, exogenous sphinganine 1-phosphate protected against both liver and kidney injury induced by liver IR. In this study, we elucidated the signaling mechanisms of sphinganine 1-phosphate-mediated renal and hepatic protection. A selective S1P1 receptor antagonist blocked the hepatic and renal protective effects of sphinganine 1-phosphate whereas a selective S1P2 or S1P3 receptor antagonist was without effect. Moreover, a selective S1P1 receptor agonist, SEW-2871, provided similar degree of liver and kidney protection compared with sphinganine-1-phosphate. Furthermore, in vivo gene knock-down of S1P1 receptors with small interfering RNA abolished the hepatic and renal protective effects of sphinganine 1-phosphate. In contrast to sphinganine 1-phosphate, S1P’s hepatic protection was enhanced with an S1P3 receptor antagonist. Inhibition of extracellular signal-regulated kinase, Akt or pertussis toxin-sensitive G-proteins blocked sphinganine-1-phosphate-mediated liver and kidney protection in vivo. Taken together, our results show that sphinganine 1-phosphate provided renal and hepatic protection after liver IR injury in mice via selective activation of S1P1 receptors and pertussis toxin-sensitive G-proteins with subsequent activation of ERK and Akt.