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Abstract: PO0942

A Hyaluronan Synthesis Inhibitor Delays the Progression of Diabetic Kidney Disease in a Mouse Experimental Model

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Salman, Loay H., Albany Medical College, Albany, New York, United States
  • Selman, Guillermo, Albany Medical College, Albany, New York, United States
  • Lightle, Andrea R., Albany Medical College, Albany, New York, United States
  • Aguilar, Alejandra E., Albany Medical College, Albany, New York, United States
  • Woltmann, Daniel R., Albany Medical College, Albany, New York, United States
  • Martinez, Laisel, University of Miami School of Medicine, Miami, Florida, United States
  • Vazquez-Padron, Roberto I., University of Miami School of Medicine, Miami, Florida, United States
Background

There is a paucity of options to treat Diabetic Kidney Disease (DKD) in the clinical practice. Hyalinosis is an important morphological feature of DKD. However, the role of hyaluronan (HA) in the development and progression of DKD as well as the precise mechanisms and consequences of HA involvement in this pathology are still to be clarified.

Methods

In this study, we assayed the effects of hyaluronan synthesis inhibitor 4-Methylumbelliferone (4-MU) on the development of DKD. As a model, we used the diabetic and moderately hypertensive endothelial nitric oxide synthase/leptin receptor deficient (eNOS- C57BLKS/Jdb) double mutant mice.

Results

At 9 weeks old, the diabetic model mice were separated into two similar groups regarding sex, body weight, non-fasting plasma glucose concentrations, and consanguinity; then, experimental animals were fed ad libitum identical artificial diets formulated by Envigo-Teklad, containing or not 5% of 4-MU sodium salt for 9 weeks. Our measures of daily food consumption show that treated animals had a dose of 270±50mg per day of 4-MU (about 6.2g/Kg body weight/day). At the end of the experimental period, we found that 4-MU-treated diabetic animals: 1) kept their average GFR, while a significant reduction of GFR was observed in diabetic controls (P=0.042, n=9/8 per group); 2) kept the average urine ACR and plasma cystatin-c values significantly lower than controls (P=0.049 (n=12 per group) and P=0.043 (n=11/10 per group) respectively); 3) had lower average kidney weight (P=0.041, n=6), and 36% less hyaluronans in kidneys (P=0.095; Effect size=1.32, n=5); and 4) 4-MU treated animals kept their body weight (final weight/maximum weight relationship) much higher than diabetic controls (P=0.002, n=16/15 per group) as well as their median survival was 6.4 weeks longer (P=0.048, n=6/5 per group). Moreover, after the treatment, an independent histopathology study showed a significant lower glomerular injury score in kidneys of 4-MU-fed animals (P=0.039, n=5/7 per group).

Conclusion

These results showed that the hyaluronan synthesis inhibitor 4-MU effectively slowed the progression of DKD. 4-MU provides a potential new therapeutic approach to treat DKD.

Funding

  • Private Foundation Support