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The kidney plays a central role in regulating the salt sensitivity of blood pressure (BP) by governing sodium excretion and reabsorption via renal sodium transporters. We hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibition and angiotensin II type 1 receptor (AT 1 R) blockade can synergistically reduce renal sodium reabsorption by beneficially effects on these transporters, leading to lower BP and ameliorating renal and cardiac damage.Methods and results: Dahl salt-sensitive rats were treated orally for 8weeks with a normal salt diet (0.3% NaCl), a high-salt diet (8% NaCl), high-salt diet with ipragliflozin (0.04%), high-salt diet with losartan (0.05%) or high-salt diet with a combination of ipragliflozin and losartan. The combination treatment significantly reduced BP and increased daily urine sodium excretion compared with losartan or ipragliflozin monotherapy, leading to greater improvement in BP salt sensitivity than ipragliflozin monotherapy. The combination treatment significantly ameliorated glomerulosclerosis and reduced cardiomyocyte hypertrophy compared with losartan or ipragliflozin monotherapy. The protein expression levels of Na þ /H þ exchanger isoform 3 (NHE3) and Na þ -K þ -CI À cotransporter 2 (NKCC2) in the kidney were significantly decreased with losartan monotherapy and combination treatment, but not with ipragliflozin monotherapy. Conclusion:Inhibition of SGLT2 in combination with an angiotensin II receptor blocker effectively improved BP salt sensitivity by reducing renal expression levels of sodium transporters including NHE3 and NKCC2, which eventually led to improvement of BP salt sensitivity and cardiorenal protection.

Background Patients with pulmonary arterial hypertension (PAH) carrying bone morphogenetic protein receptor type 2 (Bmpr2) mutations present earlier with severe hemodynamic compromise and have poorer survival outcomes than those without mutation. The mechanism underlying the worsening clinical phenotype of PAH with Bmpr2 mutations has been largely unaddressed in rat models of pulmonary hypertension (PH) because of the difficulty in reproducing progressive PH in mice and genetic modification in rats. We tested whether a clinically-relevant Bmpr2 mutation affects the progressive features of monocrotaline (MCT) induced-PH in rats. Methods A monoallelic single nucleotide insertion in exon 1 of Bmpr2 (+/44insG) was generated in rats using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9, then PH, pulmonary vascular disease (PVD) and survival after MCT injection with or without a phosphodiesterase type 5 inhibitor, tadalafil, administration were assessed. Results The +/44insG rats had reduced BMPR2 signalling in the lungs compared with wild-type. PH and PVD assessed at 3-weeks after MCT injection were similar in wild-type and +/44insG rats. However, survival at 4-weeks after MCT injection was significantly reduced in +/44insG rats. Among the rats surviving at 4-weeks after MCT administration, +/44insG rats had increased weight ratio of right ventricle to left ventricle plus septum (RV/[LV + S]) and % medial wall thickness (MWT) in pulmonary arteries (PAs). Immunohistochemical analysis showed increased vessels with Ki67-positive cells in the lungs, decreased mature and increased immature smooth muscle cell phenotype markers in the PAs in +/44insG rats compared with wild-type at 3-weeks after MCT injection. Contraction of PA in response to prostaglandin-F2α and endothelin-1 were significantly reduced in the +/44insG rats. The +/44insG rats that had received tadalafil had a worse survival with a significant increase in RV/(LV + S), %MWT in distal PAs and RV myocardial fibrosis compared with wild-type. Conclusions The present study demonstrates that the Bmpr2 mutation promotes dedifferentiation of PA smooth muscle cells, late PVD and RV myocardial fibrosis and adversely impacts both the natural and post-treatment courses of MCT-PH in rats with significant effects only in the late stages and warrants preclinical studies using this new genetic model to optimize treatment outcomes of heritable PAH.