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MORG1-A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes
Eric Jankowski1, Sophie Wulf1, Nadja Ziller1
1Department of Internal Medicine III, Jena University Hospital, Am Klinikum 1, D-07747 Jena, Germany.
Abstract:
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.
Insights
Reduced MORG1 expression protects against diabetic kidney disease by improving lipid metabolism and reducing fibrosis. This finding offers a promising therapeutic strategy for managing diabetic nephropathy in both type 1 and type 2 diabetes mellitus.
Area of Science:
- Nephrology
- Metabolic Research
- Molecular Biology
Background:
- Altered renal lipid metabolism is implicated in diabetic kidney disease (DKD) progression.
- Tubulointerstitial fibrosis (TIF) is a key pathological feature of DKD.
- MORG1, a scaffold protein in HIF and ERK signaling, has shown renoprotective effects in a type 2 diabetes model.
Purpose of the Study:
- To investigate whether reduced MORG1 expression restores renal lipid metabolism in diabetic nephropathy.
- To explore the differential impact of MORG1 deficiency on lipid metabolism in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).
Main Methods:
- Utilized a mouse model with reduced MORG1 expression.
- Assessed renal fatty acid and cholesterol metabolism.
- Evaluated markers of tubulointerstitial fibrosis (TIF), including TGF-ß1 expression and epithelial-mesenchymal transition (EMT)-like changes.
- Compared metabolic alterations in T1DM and T2DM models.
Main Results:
- Reduced MORG1 expression conferred protection against TIF in diabetic mice.
- Renal lipid metabolism dysregulation differs between T1DM and T2DM.
- T1DM showed more pronounced disruptions in de novo fatty acid/cholesterol synthesis and beta-oxidation.
- T2DM exhibited pathological fat uptake leading to lipotoxicity in tubular cells.
- MORG1 deficiency modulated TIF and lipid dysregulation to varying extents in T1DM and T2DM.
Conclusions:
- Diminished MORG1 expression provides renoprotection in diabetic nephropathy by targeting TIF and lipid metabolism.
- MORG1 plays a role in modulating distinct lipid metabolic pathways affected in T1DM and T2DM.
- Targeting MORG1 represents a potential therapeutic strategy to ameliorate lipid metabolic alterations in diabetic nephropathy.
