Dominguez Jesus, Wu Pengfei, Packer C Subah, Temm Constance, Kelly Katherine J
Departments of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Am J Physiol Renal Physiol. 2007 Sep;293(3):F670-9. doi: 10.1152/ajprenal.00021.2007. Epub 2007 Jun 27.
Anomalous inflammatory responses triggered by the metabolic syndrome cause renal injury. This discovery links renal lipid accumulation with lipotoxicity to inflammation and may explain the insidious fibrosis and cellular decay characteristic of nephropathy in the metabolic syndrome. However, it is not clear whether control of inflammation protects the kidney independently of lipid accumulation, which is a required step for lipotoxicity in hyperglycemia and dyslipidemia. We hypothesized that in rats with the metabolic syndrome, and overt nephropathy, treatment with mycophenolate mofetil (MMF; 10 mg.kg(-1).day(-1) ip for 14 wk) would reduce the abnormal renal lipid depots and limit renal inflammation and injury. We studied groups of lean and obese F1 hybrid Zucker fatty diabetic/spontaneous hypertensive heart failure (ZS) rats. MMF did not affect lean rats. In obese ZS rats, MMF did not change severe hyperglycemia or the higher kidney loads of unutilized lipid and peroxidation products. Nonetheless, MMF dramatically reduced diabetes/obesity-derived systemic and renal inflammation, limited renal size, hyperfiltration, and fibrosis. These data indicate that in rats, anti-inflammatory therapy presumably acting downstream, and independently of lipotoxicity, can effectively limit renal injury and fibrosis.
代谢综合征引发的异常炎症反应会导致肾损伤。这一发现将肾脂质蓄积与脂毒性和炎症联系起来，可能解释了代谢综合征中肾病隐匿性纤维化和细胞衰退的特征。然而，尚不清楚炎症的控制是否能独立于脂质蓄积来保护肾脏，而脂质蓄积是高血糖和血脂异常中脂毒性的一个必要步骤。我们假设，在患有代谢综合征和明显肾病的大鼠中，用霉酚酸酯（MMF；10 mg·kg⁻¹·天⁻¹，腹腔注射，共14周）治疗会减少异常肾脂质沉积，并限制肾脏炎症和损伤。我们研究了瘦型和肥胖型F1杂交Zucker脂肪糖尿病/自发性高血压心力衰竭（ZS）大鼠组。MMF对瘦型大鼠没有影响。在肥胖的ZS大鼠中，MMF并未改变严重的高血糖或未利用脂质和过氧化产物的较高肾脏负荷。尽管如此，MMF显著减轻了糖尿病/肥胖引起的全身和肾脏炎症，限制了肾脏大小、超滤和纤维化。这些数据表明，在大鼠中，抗炎治疗可能作用于下游且独立于脂毒性，可有效限制肾脏损伤和纤维化。
