流行病学研究显示，高果糖摄入与糖尿病和慢性肾脏病密切相关。糖尿病状态下多元醇途径过度激活，导致果糖在肾脏局部的富集。果糖激酶（KHK）是果糖代谢途径的关键酶，作用产生有害代谢产物如尿酸、氧化物等，造成损伤。我们的前期研究表明①高果糖饮食可诱导产生依赖于KHK的肾小管间质损伤；②KHK在糖尿病小鼠近端肾小管高表达；③KHK基因敲除糖尿病小鼠慢性肾小管间质损伤轻于野生型糖尿病小鼠。提示KHK可能是参与糖尿病发生肾脏损伤的作用环节。我们推测，糖尿病状态下，近端小管KHK上调，是肾脏易感于各种有毒物质损伤的重要环节之一。本研究拟利用糖尿病状态下造影剂急性肾损伤作为疾病研究模型，通过KHK基因敲除鼠、KHK抑制剂、体外培养过表达和缺失表达KHK蛋白的小管上皮细胞，临床肾脏病理组织等研究手段，探讨KHK途径在糖尿病状态下急性肾损害发生环节中的重要作用，为进一步阐明糖尿病肾脏损伤的复杂机制提供理论依据。

We present the hypothesis that fructokinase may have a novel role in diabetic renal disease. Fructokinase is an enzyme in fructose metabolism that is present primarily in the liver, small intestines, and proximal tubule of the kidney. Little attention has focused on the role of renal fructokinase. However, the proximal tubule may be exposed to large amounts of fructose, either via the diet, or even more so by being the site of absorption of glucose which can be converted to fructose via the aldose reductase pathway. We have preliminary evidence that in the diabetic state that fructokinase is activated in the proximal tubule, likely due to massive glucose absorption with conversion to fructose. In turn, the conversion of fructose to fructose-1-phosphate results in the production of toxic byproducts, such as uric acid and oxidants, that induce tubular injury and local inflammation. Preliminary data suggest the proximal tubular injury could have a role in acute renal disease. In this application we will test this hypothesis using fructokinase knockout mice. Specifically, we will determine the role of fructokinase in explaining the predisposition of diabetic subjects to acute kidney injury from contrast. We believe these studies are novel as they address a new mechanism for renal disease (fructokinase activation in the proximal tubule). The studies could be significant as it may provide evidence for a role for fructokinase in the mechanism of contrast-induced acute renal injury in diabetes, and could also provide a mechanism linking metabolic syndrome with acute and chronic kidney disease. Finally, our approach using fructokinase knockout mice, coupled with our preliminary data, show that the studies are feasible and achievable.