Renal fatty acid (FA) metabolism is severely altered in type 1 and 2 diabetes mellitus (T1DM and T2DM). Increasing evidence suggests that altered lipid metabolism is linked to tubulointerstitial fibrosis (TIF). Our previous work has demonstrated that mice with reduced MORG1 expression, a scaffold protein in HIF and ERK signaling, are protected against TIF in the db/db mouse model. Renal TGF-ß1 expression and EMT-like changes were reduced in mice with single-allele deficiency of MORG1. Given the well-known role of HIF and ERK signaling in metabolic regulation, here we examined whether protection was also associated with a restoration of lipid metabolism. Despite similar features of TIF in T1DM and T2DM, diabetes-associated changes in renal lipid metabolism differ between both diseases. We found that de novo synthesis of FA/cholesterol and β-oxidation were more strongly disrupted in T1DM, whereas pathological fat uptake into tubular cells mediates lipotoxicity in T2DM. Thus, diminished MORG1 expression exerts renoprotection in the diabetic nephropathy by modulating important factors of TIF and lipid dysregulation to a variable extent in T1DM and T2DM. Prospectively, targeting MORG1 appears to be a promising strategy to reduce lipid metabolic alterations in diabetic nephropathy.
Keywords: MORG1; T1DM; T2DM; WDR83; diabetic nephropathy; fatty acid metabolism; kidney; lipid metabolism; mitogen-activated protein kinase organizer 1; type 1 diabetes mellitus; type 2 diabetes mellitus.