McPherson Kasi C, Taylor Lateia, Johnson Ashley C, Didion Sean P, Geurts Aron M, Garrett Michael R, Williams Jan M
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Am J Physiol Renal Physiol. 2016 Oct 1;311(4):F793-F804. doi: 10.1152/ajprenal.00590.2015. Epub 2016 Jul 27.
The current study examined the effect of obesity on the development of renal injury within the genetic background of the Dahl salt-sensitive rat with a dysfunctional leptin receptor derived from zinc-finger nucleases (SSmutant strain). At 6 wk of age, body weight was 35% higher in the SSmutant strain compared with SS rats and remained elevated throughout the entire study. The SSmutant strain exhibited impaired glucose tolerance and increased plasma insulin levels at 6 wk of age, suggesting insulin resistance while SS rats did not. However, blood glucose levels were normal throughout the course of the study. Systolic arterial pressure (SAP) was similar between the two strains from 6 to 10 wk of age. However, by 18 wk of age, the development of hypertension was more severe in the SSmutant strain compared with SS rats (201 ± 10 vs. 155 ± 3 mmHg, respectively). Interestingly, proteinuria was substantially higher at 6 wk of age in the SSmutant strain vs. SS rats (241 ± 27 vs. 24 ± 2 mg/day, respectively) and remained elevated until the end of the study. The kidneys from the SSmutant strain displayed significant glomerular injury, including podocyte foot process effacement and lipid droplets compared with SS rats as early as 6 wk of age. By 18 wk of age, plasma creatinine levels were twofold higher in the SSmutant strain vs. SS rats, suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SSmutant strain develops podocyte injury and proteinuria independently of hyperglycemia and elevated arterial pressure that later progresses to CKD.
本研究在源自锌指核酸酶的瘦素受体功能失调的 Dahl 盐敏感大鼠（SS 突变株）的遗传背景下，研究了肥胖对肾损伤发展的影响。6 周龄时，SS 突变株的体重比 SS 大鼠高 35%，且在整个研究过程中一直保持较高水平。6 周龄时，SS 突变株表现出葡萄糖耐量受损和血浆胰岛素水平升高，提示存在胰岛素抵抗，而 SS 大鼠则没有。然而，在整个研究过程中血糖水平正常。6 至 10 周龄时，两种品系的收缩动脉压（SAP）相似。然而，到 18 周龄时，与 SS 大鼠相比，SS 突变株的高血压发展更为严重（分别为 201±10 与 155±3 mmHg）。有趣的是，6 周龄时，SS 突变株的蛋白尿水平显著高于 SS 大鼠（分别为 241±27 与 24±2 mg/天），并一直升高到研究结束。与 SS 大鼠相比，SS 突变株的肾脏早在 6 周龄时就显示出明显的肾小球损伤，包括足细胞足突消失和脂滴。到 18 周龄时，SS 突变株的血浆肌酐水平是 SS 大鼠的两倍，提示存在慢性肾脏病（CKD）。总体而言，这些结果表明，SS 突变株独立于高血糖和动脉压升高而发生足细胞损伤和蛋白尿，随后发展为 CKD。
