ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-OR120

Genetic Deletion of Myo-Inositol Oxygenase (MIOX) Rescues ob/ob Mice from the Progression of Tubulo-Interstitial Injury

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Sharma, Isha, NORTHWESTERN UNIVERSITY, CHICAGO, Illinois, United States
  • Kanwar, Yashpal S., Northwestern University Medical School, Chicago, Illinois, United States
Background

MIOX, a proximal tubular enzyme, is up-regulated in diabetic state and is involved in the pathogenesis of tubulo-interstitial injury. Previously, we reported that MIOX over-expressing mice with STZ-induced diabetes have remarkable tubulo-interstitial changes. These were largely attributed to excessive generation of ROS leading to increased activity of fibrogenic cytokines, especially in the tubulo-interstitial compartment. Such phenotypic changes were not observed in MIOX-/- mice.

Methods

Aim of this study was to assess if genetic ablation of MIOX ameliorates the progression of tubulo-interstitial injury in ob/ob mice by reducing the oxidant stress in proximal tubules. MIOX-/- mice were cross bred with ob/ob mice to generate mice with double mutation (MIOX-/-/ob/ob). Animals were sacrificed at age of 20 weeks and kidneys were harvested for various studies. Prior to sacrifice blood and urine samples were obtained.

Results

The MIOX-/-/ob/ob mice had improved levels of serum creatinine, urea and insulin compared to ob/ob mice. No change was observed in blood glucose levels. The double mutants had decreased urinary excretion of high molecular weight proteins. The MIOX expression was highly accentuated in kidneys of ob/ob mice compared to WT, and it was absent in MIOX-/- and mice with double mutation. The renal interstitial compartment had notable decreased staining of fibronectin, collagen I and III in mice with double mutation compared to ob/ob mice. The generation of ROS in the kidney tissues was notably less in MIOX-/-/ob/ob mice compared ob/ob mice, as indicated by decreased DHE staining. Analyses of various metabolic sensors revealed revival of the expression of SIRT1, AMPK, YY-1, and of the master regulator of mitochondrial biogenesis, i.e., PGC-1alpha. In vitro, HK-2 cells treated palmitate-BSA had decreased expression of various metabolic sensors with increased ROS generation, and these aberrant parameters of metabolic sensors were normalized with the treatment of MIOX-siRNA.

Conclusion

In conclusion, these findings suggest that ablation of MIOX gene ameliorates the progression of tubulo-interstitial injury in the settings of diabetic nephropathy by reducing the oxidant stress and improving the status of various metabolic sensors.

Funding

  • NIDDK Support