Kidney Week

Abstract: SA-PO122

Angiotensin-Neprilysin Inhibition Protects Glomerular Function and Structure and Lowers TRPC6 in Diabetic Hypertensive Rats

Session Information

• Diabetic Kidney Disease: Basic - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Uijl, Estrellita, Erasmus MC, Rotterdam, Netherlands

Estrellita Uijl,

• 't Hart, Daan C., Radboud university medical center, Nijmegen, Netherlands

Daan C. 't Hart,

• Roksnoer, Lodi Cw, Maasstad ziekenhuis, Rotterdam, Netherlands

Lodi Cw Roksnoer,

• Clahsen - van Groningen, Marian, Erasmus MC, Rotterdam, Netherlands

Marian Clahsen - van Groningen,

• Zietse, Robert, Erasmus Medical Center, Rotterdam, Netherlands

Robert Zietse,

• Van der vlag, Johan, Radboud University Nijmegen Medical Centre; Dept of Nephrology, Nijmegen, Gelderland, Netherlands

Johan Van der vlag,

• Nijenhuis, Tom, Radboud university medical center, Nijmegen, Netherlands

Tom Nijenhuis,

• Joles, Jaap A., University Medical Center Utrecht, Utrecht, Netherlands

Jaap A. Joles,

• Hoorn, Ewout J., Erasmus Medical Center, Rotterdam, Netherlands

Ewout J. Hoorn,

• Danser, Alexander H., Erasmus Medical Center, Rotterdam, Netherlands

Alexander H. Danser,

Background

Dual blockade with Angiotensin Receptor/Neprilysin Inhibition (ARNI) reduces glomerulosclerosis better than single AR blockade (ARB) in diabetic, hypertensive rats, but the renoprotective mechanisms remain unknown. Here, we hypothesized that this is mediated by superior blood pressure regulation, improved renal hemodynamics, protection of podocyte integrity and/or suppression of renal inflammation.

Methods

To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n=10), valsartan (n=7) or sacubitril/valsartan (ARNI; n=8) for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry.

Results

Sacubitril/valsartan lowered MAP by 50±4 mmHg and valsartan by 43±4 mmHg (P=0.3). Sacubitril/valsartan resulted in better glycemic control and lower heart weight compared to vehicle and higher urinary atrial natriuretic peptide vs. valsartan (P<0.05 for all). Histologically, sacubitril/valsartan resulted in markedly lower glomerulosclerosis scores than both valsartan and vehicle (P<0.05). Despite higher effective renal plasma flow and glomerular filtration rates, sacubitril/valsartan did not improve filtration fraction. Analysis of the renal cortex for protein abundance of the transient receptor potential cation channel C6 (TRPC6) showed ~50% reduction after sacubitril/valsartan (P=0.06 vs. vehicle). Kidney immune cell infiltration did not differ between groups.

Conclusion

In conclusion, ARNI offers drug-class specific renoprotection in a pre-clinical model of diabetes and hypertension. Renoprotection is unrelated to renal hemodynamics or inflammation but may be related to the protective effects of natriuretic peptides and/or improved glycaemia on podocyte integrity, possibly via attenuation of Ca²⁺ influx through TRPC6 channels.