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Abstract: TH-OR065

Genetic Deletion of MIOX Ameliorates Obesity-Associated Tubulointerstitial Injury via Modulating O-GlcNAcylation of Sterol Regulatory Element Binding Protein (SREBP)

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Sharma, Isha, Northwestern University Medical School, Chicago, Illinois, United States
  • Deng, Fei, Northwestern University Medical School, Chicago, United States
  • Liao, Yingjun, Northwestern University Medical School, Chicago, United States
  • Kanwar, Yashpal S., Northwestern University Medical School, Chicago, Illinois, United States
Background

Myo-inositol oxygenase (MIOX), a tubular enzyme, is involved in the pathogenesis of various forms of tubulo-interstitial injury

Methods

We assessed if genetic ablation of MIOX alone or in the background of ob/ob ameliorates obesity-associated tubulo-interstitial injury. Four weeks old Wild type (WT), MIOX overexpressing (MIOX-TG), and MIOX knockout (MIOX-KO) mice were fed HFD for four months. Also, double knockout (MIOX-/-/ob/ob) mice were evaluated at five months of age.

Results

Increased proteinuria, serum creatinine and urea was observed in HFD-fed WT and MIOX-TG, and ob/ob mice, suggestive of renal injury. These pathophysiologic parameters were normalized in HFD-treated MIOX-KO and MIOX-/-/ob/ob mice. The expression and activity of MIOX increased in the renal tubules of HFD-fed WT, MIOX-TG mice and ob/ob mice, which were associated with decreased levels of myo-inositol (MI); whereas MI levels remained relatively high in HFD-fed MIOX-KO and MIOX-/-/ob/ob mice. MIOX overexpression was accompanied with accentuated ROS generation, DNA damage, lipid and protein peroxidation. These changes were minimally observed in HFD-fed MIOX-KO and MIOX-/-/ob/ob mice. In addition, MIOX overexpression was accompanied with increased post-translational modification (O-GlcNAcylation) of cellular proteins via upregulating the expression of O-GlcNAC transferase in renal compartments in vivo. Likewise, such increase of modification of cellular proteins was observed in proximal tubular (HK-2 cells) treated with palmitate-BSA in vitro. Perturbation in cellular redox decreased the expression of various metabolic sensors, including p-AMPK, SIRT1, SIRT3, YY-1 and PGC1α, in HFD-treated MIOX-TG mice. These parameters were partially restored in HFD-fed MIOX-KO mice and MIOX-/-/ob/ob mice. Interestingly, SREBP was heavily glycosylated in HK-2 cells treated with palmitate-BSA. The SREBP exhibited a strong binding to PAI-1 promoter in HFD-fed MIOX-TG mice, leading to an increased synthesis of ECM. These aberrant metabolic and fibrogenic perturbations were normalized with MIOX gene disruption

Conclusion

In conclusion, these findings suggest that ablation of MIOX shields the kidney against obesity-induced tubulo-interstitial damage

Funding

  • NIDDK Support