AUTHOR=Gray Elizabeth Alana , Patel Sanket N. , Doris Peter A. , Hussain Tahir 

TITLE=Combining Neprilysin Inhibitor With AT2R Agonist Is Superior to Combination With AT1R Blocker in Providing Reno-Protection in Obese Rats

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.778953

DOI=10.3389/fphar.2021.778953

ISSN=1663-9812

ABSTRACT=Clinical use of the combination therapy of the neprilysin inhibitor sacubitril and angiotensin II type 1 receptor blocker valsartan is known to be associated with albuminuria. Albuminuria is both a risk factor for and an indicator of kidney injury. Earlier work from our laboratory reported that the agonist of angiotensin II type 2 receptor Compound 21 (C21) prevents proteinuria, albuminuria, and is reno-protective in obese Zucker rats fed high sodium diet (HSD). Thus, we hypothesized that sacubitril/C21 combination provides superior reno-protection compared to sacubitril/valsartan. Male obese Zucker rats 10-11 weeks old were treated daily with vehicle, sacubitril+C21, or sacubitril+valsartan while fed HSD for 16 days. HSD-feeding caused a modest increase in kidney weight and kidney dysfunction, evident by significant increases in urinary protein, osteopontin, and cystatin C. HSD-feeding lowered plasma cystatin C and creatinine concentrations suggestive of hyperfiltration, which was not affected by either treatment. Unlike sacubitril/valsartan, sacubitril/C21 treatment significantly prevented increases in proteinuria, albuminuria, and the expression of nephrin, while attenuating increases in kidney weight, independent of hyperfiltration. Moreover, sacubitril/valsartan therapy increased plasma renin and did not prevent HSD-induced increases in renal angiotensin II, while sacubitril/C21 completely prevented these changes. Together, this study suggests that sacubitril/C21 afforded superior reno-protection compared to sacubitril/valsartan therapy in high sodium-fed obese Zucker rats.