Early-Life Stress Programs a Vulnerable Renal Phenotype Under Metabolic Challenge in a Murine Model

Abstract

Early-life stress and post-weaning exposure to a high-fat diet (HFD) have been independently associated with renal abnormalities; however, little is known about how these stressors interact to increase renal susceptibility to subsequent metabolic challenges. Therefore, this study evaluated the effects of early-life stress induced by maternal separation (MS) and post-weaning HFD on renal structure and function in male C57BL/6 mice. Animals were subjected to MS or remained unmanipulated (UM) and were subsequently fed a control diet (CD) or HFD until postnatal day 133, generating four experimental groups: UM-CD, UM-HFD, MS-CD, and MS-HFD. Renal structure was assessed by renal mass, histological analysis of the renal corpuscle, stereological quantification of glomerular numerical density (Nv) and individual glomerular volume (IGV), whereas renal function was evaluated by diuresis. MS and HFD independently increased renal mass, altered diuresis, reduced glomerular Nv, and promoted glomerular hypertrophy. Histological analysis revealed mesangial expansion, narrowing of the capsular space, focal capillary obliteration, and glomeruloparietal synechiae, which were pronounced in the MS-HFD group. Two-way ANOVA showed independent effects on Nv and a significant interaction for IGV. Reduced Nv correlated with increased IGV and diuresis. These findings indicate that early-life stress and post-weaning HFD promote complementary mechanisms of glomerular remodeling, increasing susceptibility to metabolically induced renal injury.