The role of FXR in maternal obesity related renal injury in mother and offspring (#145)
The farnesoid X receptor (FXR) is a nuclear receptor known to play an important role in maintaining homeostasis of glucose and lipid metabolism. FXR activation may provide a protective role in kidney injury induced by metabolic disorders such as diabetes and obesity. We have previously demonstrated that FXR mRNA and protein are down regulated and sterol regulatory element-binding protein-1 (SREBP1) upregulated, in association with increased expression of the inflammatory cytokines monocyte chemotactic protein-1 (MCP1) and transforming growth factor-β1 (TGFß), in HK2 human proximal tubular cells (PTCs) exposed to high glucose. The FXR agonist, GW4064 ameliorates these effects. Aim We aimed to study the effect of maternal obesity on FXR expression in the offspring’s kidneys in a rat model of obesity. Methods: Pregnant female rats were fed either normal or high-fat diet and their offspring’s kidneys examined at Day 1 (birth) or Day 21 (weaning) of postnatal life. The pups’ anthropometric measures, plasma triglycerides and glucose/insulin levels were recorded at weaning. The renal structure and FXR expression, in addition to lipid droplets and fatty acid synthase expression were determined in the offspring’s kidneys. Gene expression of profibrotic, proinflammatory and metabolic markers (including FXR, TGFß, MCP1 and SREBP) were measured by real time PCR. Results: Offspring from obese rats displayed increased body weight, fat and kidney mass, blood triglycerides, and glucose intolerance compared with those from lean rats. Kidneys from offspring of obese mothers had reduced expression of FXR and increased expression of MCP1, TGFß and fatty acid synthase at Day 1, which were generally sustained at Day 21. Conclusions: Maternal obesity is associated with downregulation of renal FXR and upregulation of MCP1 and TGFß expression in the offspring’s kidneys. This effect was sustained until weaning, suggesting factors inherent in maternal obesity confer an increased risk of kidney disease in the offspring.