Abstract
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 uri
nary 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 con
trols. 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 ex
pression of Tmem144. Methylation of CpG islands in the promoter region of the
Cd300lf gene was increased (p = .001) in female F2 F0HD+F1HD offspring com
pared 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 asso
ciated 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.