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Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal α-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury. [ABSTRACT FROM AUTHOR]

The Otsuka–Long–Evans Tokushima Fatty rat represents a model for spontaneous non-insulin-dependent type II diabetes mellitus (DM), characterized by diastolic dysfunction and associated with abnormal calcium handling and decrease in sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) expression. The aim of this study was to examine whether SERCA2a gene transfer can restore the energetic deficiency and left ventricular (LV) function in this model. DM rats were randomized to receive adenovirus carrying either the SERCA2a gene (DM + Ad.SERCA2a) or the β-galactosidase gene (DM + Ad.βGal) or saline (DM + saline). LV mechanoenergetic function was measured in cross-circulated heart preparations 3 days after infection. In DM, end-systolic pressure at 0.1 ml intraballoon water (ESP0.1) was low and end-diastolic pressure at 0.1 ml intraballoon water (EDP0.1) was high (22 mm Hg), compared with non-DM (EDP0.1 12 mm Hg). In DM + Ad.SERCA2a, however, ESP0.1 was increased over 200 mm Hg and EDP0.1 was decreased to 7 mm Hg. LV relaxation rate was fast in DM + Ad.SERCA2a, but slow in the other DM groups. There was no difference in relation between cardiac oxygen consumption per beat and systolic pressure–volume area among all groups. Finally, the oxygen cost of LV contractility in DM was about three times as high as that of normal. In DM + Ad.SERCA2a, the oxygen cost decreased to control levels, but in DM + Ad.βGal/DM + saline it remained high. In DM failing hearts, the high oxygen cost indicates energy wasting, which contributes to the contractile dysfunction observed in diabetic cardiomyopathy. SERCA2a gene transfer transforms this inefficient energy utilization into a more efficient state and restores systolic and diastolic function to normal.Molecular Therapy (2006) 13, 987–996; doi: 10.1016/j.ymthe.2006.01.002 [ABSTRACT FROM AUTHOR]