Blood pressure-independent renoprotection in diabetic rats treated with AT1 receptor–neprilysin inhibition compared with AT1 receptor blockade alone

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. * ACh, : acetylcholine; ANP, : atrial natriuretic peptide; ARB, : AT1 receptor blockade; ARNI, : dual AT1 receptor–neprilysin inhibition; AT1, : angiotensin II type 1; BNP, : brain natriuretic peptide; CRC, : concentration–response curve; DM, : diabetes mellitus; EDHF, : endothelium-derived hyperpolarizing factor; eGFR, : estimated glomerular filtration rate; ENaC, : epithelial Na+ channel; ET-1, : endothelin-1; ETA/B, : endothelin type A/B; FSGS, : focal segmental glomerulosclerosis; GSI, : glomerulosclerosis index; i.p., : intraperitoneal; MAP, : mean arterial pressure; L-NAME, : N G-nitro-L-arginine methyl ester; NCC, : Na+–Cl− co-transporter; NEDD4-2, : neural-precursor-cell-expressed developmentally down-regulated 4-2; NEP, : neutral endopeptidase; NHE3, : Na+/H+ exchanger 3; NI, : NEP inhibitor; NPR, : natriuretic peptide receptor; NT-proBNP, : proBNP N-terminal end; PRA, : plasma renin activity; PRC, : plasma renin concentration; RAS, : renin–angiotensin system; SGK1, : serum- and glucocorticoid-regulated kinase 1; SNAP, : S -nitroso- N -penicillamine; TIS, : tubulointerstitial score