Abstract: TH-PO0131
Megalin as a Mediator of Diet-Induced Kidney Injury and Urate Handling Dysfunction
Session Information
- Integrative Genomics and Multi-Omics in Noncystic Genetic Kidney Disease
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Youm, Elynna B., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Shipman, Katherine E., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Lackner, Emily M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Marciszyn, Allison L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Tan, Roderick J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Weisz, Ora A., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Megalin is a multiligand receptor required for proximal tubule (PT) uptake of filtered proteins; deletion in mice leads to low molecular weight proteinuria. Beyond its role in endocytosis, we found that knockout of megalin (megKO) in PT cells alters transcription of many metabolism- and transport-related genes, suggesting that megalin mediates PT responses to diet. We previously showed that adult megKO male, but not female, mice fed a Western style diet (WD) containing high levels of fat and sucrose develop severe kidney injury. Because megKO mice placed a on a high-fat only diet do not develop kidney injury, we hypothesize that increased fructose in WD is the primary driver of diet-induced injury in megKO animals. An increased fructose diet is a risk factor for gout, which can be caused by impaired urate excretion in the PT. Recent GWAS studies have shown strong associations between variants in megalin and gout.
Methods
Aged (14-16 months) mice received a WD for 2 weeks, then tissue, serum, and urine were collected. Injury was assessed by blinded histology and qPCR. Serum and urate levels to be measured by Caraway method.
Age-matched megalin heterozygous (megHet) mice received 30% fructose (w/v) in drinking water for 3 days, with daily spot urines starting at baseline. Serum, urine, and tissue were collected at sacrifice. Serum and urate levels measured as above.
Control and megKO PT cells were incubated overnight in medium +/- 2mM fructose, collected in 80% methanol, and submitted for metabolomics.
Results
Remarkably, aged megKO mice died rapidly when fed a WD (45% mortality within 2 weeks). Of the mice that survived, both male and female megKO mice have significantly increased kidney injury compared to control mice. We found that megHet mice had increased urine urate excretion compared to control mice following 30% fructose. Metabolomics analysis revealed that megKO PT cells have increased levels of glucose-6-phosphte and α-ketoglutarate when treated overnight with 2mM fructose, compared with identically treated control cells.
Conclusion
Aged megKO mice have increased mortality on WD compared to control mice. MegKO PT cells have an aberrant metabolic response to fructose. Fructose increases urate excretion in megHet mice. These data suggest that even modest reductions in megalin expression, as in polymorphisms associated with disease, may lead to impaired metabolic response to nutritional stress.
Funding
- NIDDK Support