Dept. of Nephrology, Second Hospital of Jilin University, Changchun, China.
Am J Physiol Endocrinol Metab. 2011 Apr;300(4):E708-16. doi: 10.1152/ajpendo.00624.2010. Epub 2011 Feb 1.
12-lipoxygenase (12-LO) was implicated in the development of diabetic nephropathy (DN), in which the proteinuria was thought to be associated with a decreased expression of glomerular P-cadherin. Therefore, we investigated the role of 12-LO in the glomerular P-cadherin expression in type 2 diabetic rats according to the glomerular sizes. Rats fed with high-fat diet for 6 wk were treated with low-dose streptozotocin. Once diabetes onset, diabetic rats were treated with 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) for 8 wk. Then glomeruli were isolated from diabetic and control rats with a sieving method. RT-PCR, Western blotting, and immunofluorescent staining were used for mRNA and protein expressions of P-cadherin and angiotensin II (Ang II) type 1 receptor (AT1). We found that CDC did not affect the glucose levels but completely attenuated diabetic increases in glomerular volume and proteinuria. Diabetes significantly decreased the P-cadherin mRNA and protein expressions and increased the AT1 mRNA and protein expressions in the glomeruli. These changes were significantly prevented by CDC and recaptured by direct infusion of 12-LO product [12(S)-HETE] to normal rats for 7 days. The decreased P-cadherin expression was similar between large and small glomeruli, but the increased AT1 expression was significantly higher in the large than in the small glomeruli from diabetic and 12(S)-HETE-treated rats. Direct infusion of normal rats with Ang II for 14 days also significantly decreased the glomerular P-cadherin expression. These results suggest that diabetic proteinuria is mediated by the activation of 12-LO pathway that is partially attributed to the decreased glomerular P-cadherin expression.
12-脂氧合酶（12-LO）被认为参与了糖尿病肾病（DN）的发生发展，蛋白尿被认为与肾小球 P-钙黏蛋白表达降低有关。因此，我们根据肾小球大小，研究了 12-LO 在 2 型糖尿病大鼠肾小球 P-钙黏蛋白表达中的作用。高脂饮食喂养 6 周的大鼠给予小剂量链脲佐菌素处理。一旦糖尿病发病，用 12-LO 抑制剂肉桂酰基-3,4-二羟基-氰基肉桂酸（CDC）治疗糖尿病大鼠 8 周。然后用筛分法从糖尿病和对照组大鼠中分离肾小球。采用 RT-PCR、Western blot 和免疫荧光染色检测 P-钙黏蛋白和血管紧张素 II （Ang II）1 型受体（AT1）的 mRNA 和蛋白表达。我们发现，CDC 不影响血糖水平，但完全抑制了糖尿病大鼠肾小球体积和蛋白尿的增加。糖尿病显著降低了肾小球中 P-钙黏蛋白的 mRNA 和蛋白表达，增加了 AT1 的 mRNA 和蛋白表达。这些变化被 CDC 显著预防，并在正常大鼠中直接输注 12-LO 产物 [12（S）-HETE] 7 天而逆转。在大小肾小球中，P-钙黏蛋白表达的降低相似，但糖尿病和 12（S）-HETE 处理大鼠的大肾小球中 AT1 表达的增加明显高于小肾小球。直接输注 Ang II 14 天也显著降低了正常大鼠的肾小球 P-钙黏蛋白表达。这些结果表明，糖尿病蛋白尿是由 12-LO 途径的激活介导的，部分归因于肾小球 P-钙黏蛋白表达的降低。
