Luo Pengcheng, Zhou Yiqiang, Chang Hsin-Hsin, Zhang Jie, Seki Tsugio, Wang Cong-Yi, Inscho Edward W, Wang Mong-Heng
Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912, USA.
Am J Physiol Renal Physiol. 2009 Mar;296(3):F556-63. doi: 10.1152/ajprenal.90613.2008. Epub 2009 Jan 7.
The early stage of diabetic nephropathy (DN) is linked to proteinuria. Transforming growth factor (TGF)-beta1 increases glomerular permeability to albumin (P(alb)), whereas 20-HETE and EETs reduce P(alb). To investigate the impact of hyperglycemia and hyperlipidemia on 20-HETE, EETs, and TGF-beta1 in the glomeruli, rats were divided into four groups: ND rats were fed a normal diet, HF rats were fed a high-fat diet, STZ rats were treated with 35 mg/kg of streptozotocin, and HF/STZ rats were fed a HF diet and treated with STZ. After 10 wk on these regimens, blood glucose, urinary albumin, serum cholesterol, serum triglyceride levels, and the kidney-to-body weight ratio were significantly elevated in STZ and HF/STZ rats compared with HF and ND rats. STZ and HF/STZ rats had histopathologic changes and abnormal renal hemodynamics. Expression of glomerular CYP4A, enzymes for 20-HETE production, was significantly decreased in STZ rats, whereas expression of glomerular CYP2C and CYP2J, enzymes for EETs production, was significantly decreased in both STZ and HF/STZ rats. Moreover, glomerular TGF-beta1 levels were significantly greater in STZ and HF/STZ rats than in HF and ND rats. Five-week treatment of STZ rats with clofibrate induced glomerular CYP4A expression and 20-HETE production, but reduced glomerular TGF-beta1 and urinary protein excretion. These results demonstrate that hyperglycemia increases TGF-beta1 but decreases 20-HETE and EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DN.
糖尿病肾病（DN）的早期阶段与蛋白尿有关。转化生长因子（TGF）-β1会增加肾小球对白蛋白的通透性（P(alb)），而20-羟基二十碳四烯酸（20-HETE）和环氧二十碳三烯酸（EETs）则会降低P(alb)。为了研究高血糖和高血脂对肾小球中20-HETE、EETs和TGF-β1的影响，将大鼠分为四组：正常饮食的正常饮食组（ND）大鼠、高脂饮食的高脂饮食组（HF）大鼠、接受35mg/kg链脲佐菌素治疗的链脲佐菌素组（STZ）大鼠以及高脂饮食并接受链脲佐菌素治疗的高脂/链脲佐菌素组（HF/STZ）大鼠。在这些方案实施10周后，与HF和ND大鼠相比，STZ和HF/STZ大鼠的血糖、尿白蛋白、血清胆固醇、血清甘油三酯水平以及肾重与体重比均显著升高。STZ和HF/STZ大鼠出现了组织病理学变化和异常的肾脏血流动力学。STZ大鼠中，用于产生20-HETE的肾小球细胞色素P450 4A（CYP4A）酶的表达显著降低，而在STZ和HF/STZ大鼠中，用于产生EETs的肾小球细胞色素P450 2C（CYP2C）和细胞色素P450 2J（CYP2J）酶的表达均显著降低。此外，STZ和HF/STZ大鼠的肾小球TGF-β1水平显著高于HF和ND大鼠。用氯贝丁酯对STZ大鼠进行为期五周的治疗，可诱导肾小球CYP4A表达和20-HETE产生，但可降低肾小球TGF-β1和尿蛋白排泄。这些结果表明，高血糖会增加肾小球中TGF-β1的含量，但会降低20-HETE和EETs的产生，这些变化可能在DN早期导致肾小球损伤方面具有重要意义。
