Reperfusion after ischemia induces cytokines, chemoattractant chemokines, adhesion molecules, and nitric oxide (NO). The resultant neutrophil adherence and NO potentiates renal injury. ␣ -Melanocyte-stimulating hormone ( ␣ -MSH) is a potent anti-inflammatory agent that inhibits neutrophil migration and production of neutrophil chemokines and NO. Since neutrophils and NO promote renal ischemic injury, we sought to determine if ␣ -MSH inhibits renal injury in a model of bilateral renal ischemia. ␣ -MSH significantly reduced ischemia-induced renal damage, measured by changes in renal histology and plasma blood urea nitrogen and creatinine in mice. ␣ -MSH significantly decreased tubule necrosis, neutrophil plugging, and capillary congestion. Delay of ␣ -MSH treatment for 6 h after ischemia also significantly inhibited renal damage. ␣ -MSH also significantly inhibited ischemic damage in rats. To begin to determine the mechanism of action of ␣ -MSH, we measured its effects on media-

The secreted, cysteine-rich, heparin binding protein Cyr61 is rapidly induced in proximal straight tubules following renal ischemia, and excreted in the urine where it might serve as an early biomarker of renal injury.

There is increasing evidence that the transforming DNA tumor virus simian virus 40 (SV40) is associated with human malignancies. SV40 small tumor antigen (small t) interacts with endogenous serine/threonine protein phosphatase 2A (PP2A) and is required for the transforming activity of SV40 in epithelial cells of the lung and kidney. Here, we show that expression of SV40 small t in epithelial MDCK cells induces acute morphological changes and multilayering. Significantly, it also causes severe defects in the biogenesis and barrier properties of tight junctions (TJs) but does not prevent formation of adherens junctions. Small t-induced TJ defects are associated with a loss of PP2A from areas of cell-cell contact; altered distribution and reduced amounts of the TJ proteins ZO-1, occludin, and claudin-1; and marked disorganization of the actin cytoskeleton. Small t-mediated F-actin rearrangements encompass increased Rac-induced membrane ruffling and lamellipodia, Cdc42-initiated filopodia, and loss of Rho-dependent stress fibers. Indeed, these F-actin changes coincide with elevated levels of Rac1 and Cdc42 and decreased amounts of RhoA in small t-expressing cells. Notably, these cellular effects of small t are dependent on its interaction with endogenous PP2A. Thus, our findings provide the first evidence that, in polarized epithelial cells, expression of small t alone is sufficient to induce deregulation of Rho GTPases, F-actin, and intercellular adhesion, through interaction with endogenous PP2A. Because defects in the actin cytoskeleton and TJ disruption have been linked to loss of cell polarity and tumor invasiveness, their deregulation by PP2A and small t likely contributes to the role of SV40 in epithelial cell transformation.A majority of human tumors arise from epithelial cells. Invasion is characterized by loss of polarity, deregulation of cell adhesion, and cytoskeletal disruption. There is increasing evidence that the transforming DNA tumor virus simian virus 40 (SV40) is associated with human malignancies (17, 33). Inactivation of retinoblastoma proteins following expression of the SV40 large T antigen in MDCK cells results in an epithelialmesenchymal conversion and invasiveness (21). Studies with transgenic mice have shown that SV40 small tumor antigen (small t) cooperates with the large T antigen in inducing tumors in slowly dividing epithelial cells of the lung and kidney. Small t is also absolutely required for SV40-mediated formation of lung and kidney adenocarcinoma (2). Moreover, it promotes serum-independent cell growth in mammary gland epithelial cells and induces breast cancer formation in transgenic mice (9).Following SV40 infection (23, 30) or ectopic expression (35), small t specifically associates with endogenous serine/threonine protein phosphatase 2A (PP2A). PP2A is believed to exist in vivo predominantly as a heterotrimeric complex comprising a core enzyme containing the catalytic C and structural A subunits, which is bound to a regulatory B subunit. Significantly, distinct regulatory B ...

Gordon's syndrome, also known as pseudohypoaldosteronism type II (PHA II) or familial hypertension with hyperkalemia, is an autosomal-dominant disease characterized by hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. Recent positional cloning has linked mutations of WNK1 and WNK4 to Gordon's syndrome. With-no-lysine [K] (WNK) kinases are a new family of large serine-threonine protein kinases with an atypical placement of the catalytic lysine. Here, we review the pathogenesis of PHA II based on current understanding of the actions of WNK1 and WNK4 on Na+ and K+ handling in the renal distal tubule.

We conclude that alpha-MSH decreases renal injury when neutrophil effects are minimal or absent, indicating that alpha-MSH inhibits neutrophil-independent pathways of renal injury. The preservation of sodium absorption ex vivo and inhibition of nitrite production in cultured MCT cells suggests that alpha-MSH inhibits tubular injury by direct tubular effects.