The Influence of Sex on Early Stage Markers of Kidney Dysfunction in Response to Juvenile Obesity

Abstract

Changes within the kidney in response to obesity are critical in determining the magnitude of later dysfunction. However, the cause of this process in response to juvenile onset obesity and how it can be determined by sex is poorly understood. We therefore examined the effect of juvenile obesity induced by exposure to a restricted activity environment from weaning until early adulthood on the molecular responses within the kidney together with glomerular area and nucleated cell number. This was stratified by sex and was undertaken in a sheep model of early obesity. Despite a similar magnitude of increase in fat mass with obesity onset between sexes, adverse effects on glomerular area and cell number together with raised gene expression within the kidney only occurred in males. Irrespective of obesity, gene expression of C-C motif receptor 2 was higher, and interleukin-6 lower, in male kidneys compared with female kidneys. The effects of sex on molecular differences within the kidney were amplified with obesity, which had no effect on any gene studied in females but had an enhanced response in males. Obese males therefore showed increased gene expression of a range of markers relating to the glucocorticoid axis, inflammation, and lipid sensing. In conclusion, young females were protected from adverse renal effects of obesity, which results in very little inflammatory or related responses. Our findings emphasize the critical importance of sex specificity in disease pathogenesis. An increased understanding of the specific mechanisms will have important implications for therapeutic strategies aimed at preventing adverse consequences of obesity.