Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China.
Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
FASEB J. 2022 Apr;36(4):e22259. doi: 10.1096/fj.202101789RR.
Effects of feeding male rats during spermatogenesis a high-fat, high-sucrose and high-salt diet (HFSSD) over two generations (F0 and F1) on renal outcomes are unknown. Male F0 and F1 rats were fed either control diet (F0CD+F1CD) or HFSSD (F0HD+F1HD). The outcomes were glomerular filtration rate and urinary albumin excretion in F1 and F2 offspring. If both outcomes were altered a morphological and molecular assessment was done. F2 offspring of both sexes had a decreased GFR. However, increased urinary albumin excretion was only observed in female F2 F0HD+F1HD offspring compared with controls. F0HD+F1HD female F2 offspring developed glomerulosclerosis (+31%; p < .01) and increased renal interstitial fibrosis (+52%; p < .05). RNA sequencing followed by qRT-PCR validation showed that four genes (Enpp6, Tmem144, Cd300lf, and Actr3b) were differentially regulated in the kidneys of female F2 offspring. lncRNA XR-146683.1 expression decreased in female F0HD+F1HD F2 offspring and its expression was (r = 0.44, p = .027) correlated with the expression of Tmem144. Methylation of CpG islands in the promoter region of the Cd300lf gene was increased (p = .001) in female F2 F0HD+F1HD offspring compared to controls. Promoter CpG island methylation rate of Cd300lf was inversely correlated with Cd300lf mRNA expression in F2 female offspring (r = -0.483, p = .012). Cd300lf mRNA expression was inversely correlated with the urinary albumin-to-creatinine ratio in female F2 offspring (r = -0.588, p = .005). Paternal pre-conceptional unhealthy diet given for two generations predispose female F2 offspring to chronic kidney disease due to epigenetic alterations of renal gene expression. Particularly, Cd300lf gene promotor methylation was inversely associated with Cd300lf mRNA expression and Cd300lf mRNA expression itself was inversely associated with urinary albumin excretion in F2 female offspring whose fathers and grandfathers got a pre-conceptional unhealthy diet.
两代（F0 和 F1）雄性大鼠在精子发生期给予高脂肪、高蔗糖和高盐饮食（HFSSD）对肾脏结局的影响尚不清楚。雄性 F0 和 F1 大鼠分别给予对照饮食（F0CD+F1CD）或 HFSSD（F0HD+F1HD）。结果是 F1 和 F2 后代的肾小球滤过率和尿白蛋白排泄。如果这两种结果都发生改变，则进行形态学和分子评估。F2 后代的肾小球滤过率均降低。然而，与对照组相比，仅在雌性 F2F0HD+F1HD 后代中观察到尿白蛋白排泄增加。F0HD+F1HD 雌性 F2 后代出现肾小球硬化症（增加 31%；p<.01）和肾间质纤维化增加（增加 52%；p<.05）。RNA 测序和 qRT-PCR 验证表明，在雌性 F2 后代的肾脏中，有四个基因（Enpp6、Tmem144、Cd300lf 和 Actr3b）的表达发生了差异调节。F0HD+F1HD F2 雌性后代的 lncRNA XR-146683.1 表达减少，其表达与 Tmem144 的表达呈正相关（r=0.44，p=0.027）。与对照组相比，Cd300lf 基因启动子区 CpG 岛的甲基化增加（p=0.001）。F2F0HD+F1HD 雌性后代的 Cd300lf 基因启动子 CpG 岛甲基化率与 F2 雌性后代的 Cd300lf mRNA 表达呈负相关（r=-0.483，p=0.012）。Cd300lf mRNA 表达与雌性 F2 后代的尿白蛋白与肌酐比值呈负相关（r=-0.588，p=0.005）。两代雄性大鼠在精子发生期给予的父系孕前不健康饮食会导致雌性 F2 后代发生慢性肾病，这是由于肾脏基因表达的表观遗传改变所致。特别是，Cd300lf 基因启动子甲基化与 Cd300lf mRNA 表达呈负相关，而 Cd300lf mRNA 表达本身与 F2 雌性后代的尿白蛋白排泄呈负相关，其父亲和祖父在孕前接受了不健康饮食。
