Aldose reductase, a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications in diabetes. Despite recent studies from our laboratory demonstrating protection of ischemic hearts by an aldose reductase inhibitor, the presence and influence of aldose reductase in cardiac tissue remain unknown. Our goal in this study was to isolate and characterize the kinetic properties of cardiac aldose reductase, as well as to study the impact of flux via this enzyme on glucose metabolism and contractile function in hearts subjected to ischemia-reperfusion. Results demonstrate that ischemia increases myocardial aldose reductase activity and that these increases are, in part, due to activation by nitric oxide. The kinetic parameter of cardiac aldose reductase (Kcat) was significantly higher in ischemic tissues. Aldose reductase inhibition increased glycolysis and glucose oxidation. Aldose reductase inhibited hearts, when subjected to ischemia/reperfusion, exhibited less ischemic injury and was associated with lower lactate/pyruvate ratios (a measure of cytosolic NADH/NAD+), greater tissue content of adenosine triphosphate, and improved cardiac function. These findings indicate that aldose reductase is a component of ischemic injury and that pharmacological inhibitors of aldose reductase present a novel adjunctive approach for protecting ischemic hearts.

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Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor. Previous studies have shown that decreased ocular levels of PEDF are associated with diabetic retinopathy. However, the implication of PEDF expression in diabetic nephropathy has not been revealed. In the present study, we demonstrated for the first time that the expression of PEDF was decreased at both the mRNA and protein levels in the kidney of diabetic rats, whereas transforming growth factor-␤ (TGF-␤) and fibronectin levels were increased in the same diabetic kidneys. As shown by immunohistochemistry, the decrease of PEDF expression occurs primarily in the glomeruli. In vitro studies showed that high concentrations of glucose significantly decreased PEDF secretion in primary human glomerular mesangial cells (HMCs), suggesting that hyperglycemia is a direct cause of the PEDF decrease in the kidney. Toward the function of PEDF, we showed that PEDF blocked the highglucose-induced overexpression of TGF-␤, a major pathogenic factor in diabetic nephropathy, and fibronectin in primary HMCs, suggesting that PEDF may function as an endogenous inhibitor of TGF-␤ expression and fibronectin production in glomeruli. Therefore, decreased expression of PEDF in diabetic kidneys may contribute to extracellular matrix overproduction and the development of diabetic nephropathy. Diabetes 54: [243][244][245][246][247][248][249][250] 2005

While some studies have suggested that hematopoietic stem cells might give rise to other tissue types, others indicate that transdifferentiation would have to be an extremely rare event. We have now exploited smooth muscle type ␣-actin (␣SMA) promoter-driven green fluorescent protein (GFP) transgenic mice (␣SMA-GFP mice) for bone marrow transplantation to evaluate their potential to generate donor-type tissues in irradiation chimeras. There was a highly restricted pattern of GFP expression in the transgenic mice, marking bone marrow stromal cells and mesangial cells in the kidney. However, these characteristics were not transferable to wild-type animals given transgenic marrow cells even though hematopoietic cells were largely replaced. Our findings support earlier studies suggesting that the bone marrow microenvironment is difficult to transplant and indicate that hematopoietic stem cells are unlikely to give rise to ␣SMA-expressing progeny. STEM CELLS 2006;24:13-22

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The distribution of NADPH-dependent reductase activity in the rat cortex, outer medulla and inner medulla was investigated through biochemical and histochemical methods. Biochemical studies revealed reductase activity to be present in all three regions of the kidney with the highest specific activity observed in the inner medulla, followed by the cortex and the outer medulla. Activity in all three regions was inhibited by the aldose reductase inhibitors sorbinil, tolrestat and 7-hydroxychromone-2-carboxylic acid. Based on substrate utilization and response to sulfate on the inhibitors, the inner medulla contains primarily aldose reductase (EC 1.1.1.21) while the cortex contains primarily aldehyde reductase (EC 1.1.1.2). The outer medulla contains a mixture of both enzymes. This distribution was confirmed by a radioimmunoassay for aldose reductase. Immunohistochemical investigations of the rat kidney with antibodies against rat lens aldose reductase and rat kidney aldehyde reductase revealed a similar distribution of these enzymes. Aldehyde reductase was immunohistochemically detected only in the cortex where it was localized in the proximal convoluted tubules. Immunoreactive aldose reductase was detected in Henle's loop at both the inner stripe of the outer medulla and in the inner medulla, and in the collecting tubules and the epithelial cell lining the pelvis of the inner medulla near the papilla. No specific immunohistochemical staining for aldose reductase was observed in the cortex. A similar immunohistochemical distribution of aldose reductase was also observed in the human kidney with antibodies against human placental aldose reductase.

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