Kidney outcomes are altered by preconception weight modulation in rodent mothers with obesity

Abstract

Obesity increases the risk of chronic kidney disease. We have previously demonstrated the benefits of preconception maternal weight loss on fertility and pregnancy outcomes in a mouse model of maternal obesity. Here, we elucidate if preconception weight loss, either by diet modification or the glucose-like peptide 1 agonist liraglutide, used in the treatment of diabetes and obesity, improves maternal kidney outcomes in late gestation. C57BL/6 female mice were fed either a high-fat-diet (HFD) or a chow (control) diet for 8 weeks. To induce pre-pregnancy weight loss, HFD-fed dams were switched to chow diet (HFD-C) or administered liraglutide (0.3 mg/kg subcutaneous) whilst continuing on HFD (HFD-L). Liraglutide was discontinued one week prior to mating. HFD-V mice continued on HFD, with saline injections. A group of HFD-fed dams were ‘diet switched’ to chow after conception (post-conception, HFD-PC). Maternal body weight and glucose tolerance were measured: (1) preconception and (2) during late gestation followed by blood, urine and kidney collection. Serum creatinine, urinary creatinine and albumin, kidney tissue gene expression and protein were measured. In the preconception period, HFD-L and HFD-C mothers have lower urine albumin:creatinine ratios (UACR) and fatty acid synthase (FAS) protein expression (P < 0.005 vs. HFD-V). At late gestation, kidneys of HFD-V and HFD-PC dams have increased gene expression of insulin receptor and FAS (P < 0.05) and higher UACR compared to controls (P < 0.01). In the HFD-PC group, kidneys show increased mRNA and protein expression of metabolic and oxidative stress markers (FAS, 8-OHdG vs. control, P < 0.05, P < 0.0001 respectively). The preconception intervention groups with liraglutide, or diet change show reduced oxidative stress (protein expression of 8-OHdG, P < 0.05 vs. HFD), mRNA and protein expression of FAS (P < 0.05 vs. HFD), protein expression of fibrosis markers (collagen IV, fibronectin vs. HFD, P < 0.05), and UACR (P < 0.05 vs. HFD). This study suggests that preconception weight loss benefits maternal kidney health during pregnancy, superior to diet intervention once already pregnant.