Abstract: TH-PO196
Differential Expression of Myo-Inositol Oxygenase (MIOX) Modulates Severity of Obesity-Associated Diabetic Nephropathy in Mice
Session Information
- Diabetic Kidney Disease: Basic - I
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Sharma, Isha, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Kanwar, Yashpal S., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background
Myo-inositol oxygenase (MIOX) is predominantly expressed in renal proximal tubules. Overexpression of MIOX in the setting of diabetes leads to exacerbation of renal injury; conversely genetic ablation of MIOX lessens the progression of nephropathy.
Methods
Six-weeks-old, wild type (WT), MIOX overexpressing (MIOX-TG) and MIOX-knockout (MIOX-KO) mice were fed with high fat diet (HFD) for 16 weeks. In addition, ob/ob mice were bred with MIOX-KO to generate ob/KO mice.
Results
We observed that MIOX deletion had no effect on obesity-driven phenotypes including body weight, triacylglycerol, cholesterol or insulin levels. Interestingly, MIOX-KO and ob/KO had reduced HFD-induced renal damage, as assessed in H & E and PAS-stained kidney sections. Obese WT and MIOX overexpressing mice showed proteinuria assessed by SDS-PAGE, which was reduced in mice with MIOX deletion. In addition, tubular injury, as assessed by increased NGAL and Kim-1 expression was reduced after MIOX deletion. No significant change was observed in serum creatinine or urea levels among various strains of mice. MIOX expression and activity increased following HFD administration, which was accompanied by increased ROS generation and perturbed redox potential in kidney. The Reactive oxygen species-mediated damage caused by lipid peroxidation and lipoprotein toxicity was reduced in mice with MIOX genetic deletion. In addition, we observed MIOX overexpression increased O-GlcNacylation of renal proteins, which was substantially less in MIOX-KO mice. Interestingly, MIOX-TG mice showed increased SREBP-1 expression. Results of co-immunoprecipitation suggested that SREBP-1 is stabilized by O-GlcNacylation. SREBP-1 transient knockdown in Palmitate BSA treated HK-2 cells attenuated fibronectin deposition. Results of immunofluorescence studies suggested that MIOX-KO and ob/KO mice had considerably decreased expression of fibronectin compared to WT or MIOX-overexpressor mice
Conclusion
Together, our results suggest that some of the renal damage observed in the setting of obesity are ameliorated following MIOX gene disruption, and support pharmacologic downregulation of MIOX activity as a candidate therapy.
Funding
- NIDDK Support