MethodsMice. nu/nu mice (B6.Cg-Foxn1 nu )and C57BL/6 wild-type littermates were purchased from The Jackson Laboratory (Bar Harbor, Maine, USA). The two main defects of Leukocytes have been implicated in the pathogenesis of ischemic acute renal failure (ARF), but the roles of the individual cell types involved are largely unknown. Recent indirect evidence suggests that T cells may play an important role in a murine model of ARF. In the current study, we found that mice deficient in T cells (nu/nu mice) are both functionally and structurally protected from postischemic renal injury. Reconstitution of nu/nu mice with wild-type T cells restored postischemic injury. We then analyzed the contribution of the individual T cell subsets to postischemic injury and found that mice deficient in CD4 + T cells, but not mice deficient in CD8 + T cells, were significantly protected from ARF. Direct evidence for a pathophysiologic role of the CD4 + T cell was obtained when reconstitution of CD4-deficient mice with wild-type CD4 + T cells restored postischemic injury. In addition, adoptive transfers of CD4 + T cells lacking either the costimulatory molecule CD28 or the ability to produce IFN-γ were inadequate to restore injury phenotype. These results demonstrate that the CD4 + T cell is an important mediator of ischemic ARF, and targeting this cell may yield novel therapies.

The development of precise connectivity patterns during the establishment of the nervous system depends on the regulated action of diverse, conserved families of guidance cues and their neuronal receptors. Determining how these signaling pathways function to regulate axon growth and guidance is fundamentally important to understanding wiring specificity in the nervous system and will undoubtedly shed light on many neural developmental disorders. Considerable progress has been made in defining the mechanisms that regulate the correct spatial and temporal distribution of guidance receptors and how these receptors in turn signal to the growth cone cytoskeleton to control steering decisions. This review focuses on recent advances in our understanding of the mechanisms mediating growth cone guidance with a particular emphasis on the control of guidance receptor regulation and signaling.

Mononuclear cell infiltrates are found in human renal ischemia-reperfusion injury (IRI), and peritubular T lymphocytes have been identified in experimental IRI. However, the role of T cells in the pathogenesis of renal IRI is unknown. We hypothesized that T cells are one of the important mediators of renal IRI. To test this hypothesis, we used an established mouse model of renal IRI, and evaluated mice with genetically engineered deficiency of both CD4+ and CD8+ T cells. At 48 h postischemia, CD4/CD8-knockout (KO) mice had marked improvement in renal function compared with control C57BL/6 mice (serum creatinine: 0.7 +/- 0.4 vs. 2.5 +/- 0.3 mg/dl, respectively; P < 0.05). Neutrophil infiltration into postischemic kidney was reduced in CD4/CD8 KO mice, compared with control mice, at both 24 h [polymorphonuclear neutrophils (PMNs)/10 high power fields: 714 +/- 354 vs. 3,514 +/- 660, respectively; P < 0.05] and 48 h (88 +/- 32 vs. 1,979 +/- 209, respectively; P < 0.05). Tubular necrosis score in CD4/CD8 KO mice, compared with control mice, was significantly less at 48 h (0.4 +/- 0.1 vs. 2.4 +/- 0.2, respectively; P < 0.05). Because adhesion between T cells and renal tubular epithelial cells (RTECs) may underlie the pathophysiological role of T cells in renal IRI, we also measured T cell adhesion to primary murine RTECs in vitro. Exposure of RTECs to 2 h of hypoxia followed by 1 h of reoxygenation increased T cell adhesion more than twofold. Phorbol ester treatment, which activates integrins, increased T cell adhesion threefold. These data suggest that T lymphocytes can mediate experimental renal IRI. Moreover, adhesion of infiltrating T cells to renal tubular cells may provide a potential mechanism underlying postischemic tubular dysfunction.

Hyperlipidemic obese Zucker rats develop albuminuria and spontaneous focal glomerulosclerosis (FGS) at an early age, despite normal glomerular capillary pressures and nephron plasma flows. To investigate the role of abnormal lipid metabolism in the pathogenesis of FGS, pharmacologic agents were used to reduce serum lipids in male, obese Zucker rats. Eight rats were treated from 8 to 40 weeks of age with the cholesterol synthesis inhibitor, mevinolin (group I). A separate group of seven obese rats was treated with the structurally-unrelated lipid lowering agent, clofibric acid (group II). Results from these two groups were compared to controls injected with vehicle only (group III). Body weight and food intake were similar in all three groups. Mevinolin reduced both serum cholesterol and fasting triglyceride levels while clofibric acid lowered only serum cholesterol. Urine albumin excretion was reduced in groups I and II compared to group III. Mesangial matrix expansion and cellularity were both reduced by mevinolin and clofibric acid. In addition, the percent of glomeruli with focal glomerulosclerosis was much less in groups I (0.4 +/- 0.1%) and II (1.3 +/- 0.7%) compared to group III (4.6 +/- 0.7%, P less than 0.05). Micropuncture studies, carried out in separate groups of obese rats, demonstrated that mevinolin and clofibric acid did not affect glomerular hemodynamic function. Although the precise mechanism remains to be defined, these results suggest that abnormal lipid metabolism may be important in the pathogenesis of FGS.