title: Blood pressure-independent renoprotection in diabetic rats treated with AT1 receptor-neprilysin inhibition compared with AT1 receptor blockade alone.
abstract: ARNI [dual AT1 (angiotensin II type 1) receptor-neprilysin inhibition] exerts beneficial effects on blood pressure and kidney function in heart failure, compared with ARB (AT1 receptor blockade) alone. We hypothesized that ARNI improves cardiac and kidney parameters in diabetic TGR(mREN2)27 rats, an angiotensin II-dependent hypertension model. Rats were made diabetic with streptozotocin for 5 or 12 weeks. In the final 3 weeks, rats were treated with vehicle, irbesartan (ARB) or irbesartan+thiorphan (ARNI). Blood pressure, measured by telemetry in the 5-week group, was lowered identically by ARB and ARNI. The heart weight/tibia length ratio in 12-week diabetic animals was lower after ARNI compared with after ARB. Proteinuria and albuminuria were observed from 8 weeks of diabetes onwards. ARNI reduced proteinuria more strongly than ARB, and a similar trend was seen for albuminuria. Kidneys of ARNI-treated animals showed less severe segmental glomerulosclerosis than those of ARB-treated animals. After 12 weeks, no differences between ARNI- and ARB-treated animals were found regarding diuresis, natriuresis, plasma endothelin-1, vascular reactivity (acetylcholine response) or kidney sodium transporters. Only ARNI-treated rats displayed endothelin type B receptor-mediated vasodilation. In conclusion, ARNI reduces proteinuria, glomerulosclerosis and heart weight in diabetic TGR(mREN2)27 rats more strongly than does ARB, and this occurs independently of blood pressure.
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Lodi C W
authors.initials: LC
authors.lastname: Roksnoer
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Veghel
authors.affiliation: Department of Pathology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Clahsen-van Groningen
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Usha M
authors.initials: UM
authors.lastname: Bhaggoe
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Jeanette M G
authors.initials: JM
authors.lastname: van Gool
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Edith C H
authors.initials: EC
authors.lastname: Friesema
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Frank P J
authors.initials: FP
authors.lastname: Leijten
authors.affiliation: Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands a.danser@erasmusmc.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Batenburg
mesh_terms: D000613:Aminobutyrates / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004338:Drug Combinations; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013777:Tetrazoles / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D013311:Streptozocin; D000068756:Valsartan; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: AT1 receptor antagonist; diabetes; hypertension; neprilysin inhibition; renin–angiotensin system