High‐fat, sucrose and salt‐rich diet during rat spermatogenesis lead to the development of chronic kidney disease in the female offspring of the F2 generation

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 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.

Parental sex-dependent effects of either maternal or paternal eNOS deficiency on the offspring’s phenotype without transmission of the parental eNOS deficiency to the offspring

“…A novel mechanism, initially proposed by Hocher et al (2000) and subsequently validated by other researchers ( Masuda et al, 2002 ; van Beynum et al, 2006 ; Tsai et al, 2008 ; Miodovnik et al, 2012 ; Warrington et al, 2019 ), suggests that maternal genes may influence the fetal phenotype independently of the fetal genome. Similarly, existing studies have already suggested that paternal genes, even without being transmitted to the offspring, may also influence the phenotype of the offspring ( Nelson et al, 2010 ; Chen et al, 2012 ; Li et al, 2016 ; Zhang et al, 2019 ; Liu et al, 2021 ; Zhang et al, 2022 ).…”

Developmental origins of health and disease: Impact of paternal nutrition and lifestyle

“…44 Moreover, paternal HFD-induced obesity is associated with renal triglyceride accumulation and histological changes in tubules, accompanied by upregulated expression of acetyl-CoA acetyltransferase 1, and epigenetic alterations of renal mRNA expression of genes (Enpp6, Tmem144, Cd300lf, and Actr3b) in offspring, implying a higher risk of chronic kidney disease. 45,46 High sugar intake…”

“…Further investigation on the brain has demonstrated that male exposure to the HFD may contribute to stable behavioral variation among females in courtship, maternal care, and anxiety‐like behavior, 43 as well as cognitive impairments in the offspring due to altered methylation and expression of the BDNF gene 44 . Moreover, paternal HFD‐induced obesity is associated with renal triglyceride accumulation and histological changes in tubules, accompanied by upregulated expression of acetyl‐CoA acetyltransferase 1, and epigenetic alterations of renal mRNA expression of genes ( Enpp6 , Tmem144 , Cd300lf , and Actr3b ) in offspring, implying a higher risk of chronic kidney disease 45,46 …”

Maternal High-Fat Diet Controls Offspring Kidney Health and Disease

“…In some studies, a maternal high-fat diet was applied as the first hit, followed by a second hit to induce kidney disease in later life. For instance, animal models of a maternal and postnatal high-fat diet [ 82 ] and a combined maternal high-fat, high-sucrose, and high-salt diet [ 83 ] have been used to study renal programming. Another hit may trigger the same programming mechanisms and amplify adverse actions culminating in a disease state.…”