Abstract: FR-PO626

Renal and Cardiovascular Dysfunction in db/db Diabetic Mice Is Associated with Increased Cardiac Angiotensin Converting Enzyme 2 (ACE2) and Neprilysin (NEP)

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Fadnavis, Rucha, Wright State University, Dayton, Ohio, United States
  • Kumbaji, Meenasri, Wright State University, Dayton, Ohio, United States
  • El-Amouri, Salim, Wright State University, Dayton, Ohio, United States
  • Grobe, Nadja, Wright State University, Dayton, Ohio, United States
  • Elased, Khalid M., Wright State University, Dayton, Ohio, United States
Background

The prevalence of diabetic kidney disease (DKD) has increased in the recent decades and is considered one of the main causes of ESRD. DKD is also a major risk factor for cardiovascular diseases. Proteinuria is now widely accepted as an independent risk factor for cardiovascular morbidity and mortality. The renin angiotensin system (RAS) plays an important role in regulating both the renal and cardiovascular systems. The deleterious actions of Ang II are antagonized by Ang (1-7), which is generated by ACE2 and NEP. ACE2 and NEP are multifunctional enzymes and their shedding in the urine have emerged as early biomarkers for DKD. ACE2 has been shown to have renoprotective and cardioprotective role in diabetic mice. In addition, a combination of AT1 receptor blockade and NEP inhibition, Sacubitril-Valsartan is used for management of heart failure . The aim of this study was to investigate whether shedding of urinary ACE2 and NEP could be a predictor of cardiovascular disease and index of intra cardiac ACE2 and NEP status in db/db diabetic mice.

Methods

Radio-telemetry was used to measure blood pressure. Control and diabetic db/db mice (8 weeks) were treated with pioglitazone (20mg/Kg/day) for 10 weeks. Western blot, immunostaining and RAS enzyme assays were used to study renal, urinary and cardiac protein expression and activities.

Results

db/db mice are normotensive at the ages of 8-12 weeks. There were no significant differences in cardiac ACE2 and NEP between db/db and control mice. However, at 18 weeks, db/db mice developed albuminuria and hypertension. In addition, at this age there was a significant increase in urinary and cardiac ACE2, NEP expression and activity. Pioglitazone treatment of db/db diabetic mice normalized hyperglycemia and attenuated albuminuria. In addition, pioglitazone increased expression and activity of cardiac ACE2 whereas it decreased expression and activity of cardiac NEP compared to untreated db/db mice.

Conclusion

Pioglitazone treatment could be used as a renoprotective and cardioprotective since it attenuated albuminuria, increased cardiac ACE2 and decreased cardiac NEP. Increased urinary ACE2 and NEP could be used to predict alteration of cardiac RAS status and possible risk of cardiovascular diseases.