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Abstract: PO2037

Combination Therapy of Neprilysin Inhibitor with AT2R Agonist C21 Provides Superior Renoprotection Compared to its Combination with AT1R Antagonist Valsartan in High-Sodium Diet-Fed Obese Zucker Rats

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)


  • Gray, Elizabeth Alana, University of Houston, Houston, Texas, United States
  • Patel, Sanket Niranjanbhai, University of Houston, Houston, Texas, United States
  • Hussain, Tahir, University of Houston, Houston, Texas, United States

The neprilysin (NEP) inhibitor sacubitril (SAC) combined with the angiotensin II type 1 receptor (AT1R) blocker valsartan (VAL) (i.e. Entresto) is clinically approved for the treatment of heart failure (HF) associated with reduced ejection fraction, owing mainly to its ability to preserve atrial natriuretic peptide (ANP), a substrate of NEP. However, many HF patients treated with Entresto have presented with increased albuminuria. We have reported that the agonist of angiotensin II type 2 receptor (AT2R) Compound 21 (C21) prevents proteinuria and is reno-protective in obese Zucker rats (OZR) fed high sodium diet (HSD). Thus, we hypothesized that SAC/C21 combination provides superior reno-protection compared to the current SAC/VAL therapy.


Male OZR 10-11 wks. old were treated daily via oral gavage with vehicle, SAC (10mg/kg/day) + C21 (1mg/kg/day), or SAC (10mg/kg/day) + VAL (10mg/kg/day) while fed HSD (4%) for 16 days.


Untreated HSD-fed OZR showed reduced plasma ANP and increases in renal cortical Ang II (all p<0.05 vs OZR-fed 0.4% normal sodium diet (NSD)). These changes were associated with a modest increase in kidney weight and kidney dysfunction, evident by increased proteinuria, and reduced urinary excretion of urea nitrogen and creatinine (all p<0.05 vs OZR-fed NSD). Other indices of renal injury include increased cortical expression of nephrin (p<0.05 vs OZR-fed NSD), podocin, megalin, albuminuria, and increased urinary osteopontin (OPN). Treatment with SAC/C21 significantly prevented increases in renal Ang II, proteinuria, albuminuria, nephrin expression and kidney weight (all p<0.05 vs OZR-fed HSD), while SAC/VAL did not affect these parameters. Furthermore, SAC/C21 prevented the decline in the excretion of urinary creatinine and decreased urinary OPN (all p<0.05 vs SAC/VAL). Moreover, SAC/VAL therapy increased plasma renin concentrations ~3-fold compared to OZR-fed HSD and SAC/C21.


Together, this study suggests that combination therapy with SAC/C21 afforded superior reno-protection compared to SAC/VAL therapy in HSD-fed OZR.


  • NIDDK Support