MORG1 Haploinsufficiency Is Associated with Stage- and Sex-Dependent Renoprotection and Signalling Alterations in...

Type 2 diabetes mellitus (T2DM) is a major age-associated metabolic disease, and aging substantially contributes to the increasing burden and progression of chronic complications, including diabetic kidney disease (DKD). However, the molecular mechanisms underlying changes in renal susceptibility during disease progression remain incompletely understood. We hypothesized that the scaffold protein mitogen-activated protein kinase organizer 1 (MORG1/WDR83) contributes to stage-dependent differences in DKD and that these effects may vary according to biological sex. Heterozygous Morg1 deletion was introduced into the diabetic C57BLKS/J db/db mouse model, and male and female mice were analysed at early and later disease stages alongside non-diabetic controls. Renal fibrosis, albuminuria, HIF-1α expression, mTORC1 and ERK1/2 activity, and renal cortical gene expression were assessed. Morg1 haploinsufficiency was associated with reduced renal fibrosis and albuminuria during early diabetes, whereas these protective effects were less evident in later-stage diabetic animals. HIF-1α expression decreased during progression in most groups but was relatively preserved in later-stage female Morg1 heterozygotes, whereas mTORC1 and ERK1/2 signalling was altered in a genotype- and stage-dependent manner. These findings identify MORG1 as a context-dependent modifier of DKD whose renoprotective effects change across disease progression, linking MORG1-associated signalling to the evolving renal phenotype of an age-associated metabolic disease.