Cardiorenal protective effects of sodium-glucose cotransporter 2 inhibition in combination with angiotensin II type 1 receptor blockade in salt-sensitive Dahl rats

Abstract

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.

Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of Action and Efficacy in Non-Diabetic Kidney Disease from Bench to Bed-Side

“…Ipragliflozin (0.04%) monotherapy during eight weeks of a high-salt diet did not improve renal glomerulosclerosis or creatinine clearance in Dahl saltsensitive rats. However, the combination therapy of ipragliflozin and losartan significantly ameliorated glomerulosclerosis compared with ipragliflozin or losartan monotherapy [61].…”

“…[44] -Hypertensive and proteinuric renin-transgenic (mRen2)27 rats with additional administration of nitric oxide synthase inhibitor -Reduced proteinuria and induced protection for renal vasculopathy, glomerulopathy, and tubular degeneration [51] -Rats with renal ischemia-reperfusion injury -Reduced renal tubular dilatation and necrosis [52] -Rats with renal ischemia-reperfusion injury -Attenuated renal injury with reduced oxidative stress, inflammation an apoptosis [53] -C57/BL6 mice subjected to renal ischemia-reperfusion injury -Protected against renal injury, attenuated tubular damage, reduced inflammatory markers and inhibited apoptosis [54] -Mouse model of Alport syndrome -Reduced podocyte lipotoxicity prevented renal lipid accumulation and improved renal function [55] -Apo E−/− mice with vascular calcification and 5/6 nephrectomy -Improved renal function [56] -C57BL/6N mice with oxalate-related nephrocalcinosis -Did not affect chronic kidney disease progression in oxalate-related nephrocalcinosis [57] -Fawn-hooded hypertensive rats-Uni-nephrectomized salt-loaded rats-Rats with Goldblatt hypertension -Did not provide renoprotection because it did not ameliorate proteinuria, elevated plasma urea and creatinine, oxidative stress or inflammation [58] Ipragliflozin -C57BL/6JJcl mice with adenine induced chronic kidney disease -Renoprotective effect that was independent from plasma glucose levels and urinary glucose excretion [59] -Mouse (FLS-ob/ob) model of non-alcoholic steatohepatitis -Improved the pathogenesis of chronic kidney disease by reducing ectopic lipid deposition in renal tubules, endoplasmic reticulum stress [60] -Dahl Salt sensitive rats -Did not improve renal glomerulosclerosis or creatinine clearance [61] 3. SGLT2 and Non-Diabetic Kidney Dysfunction-Clinical Trials (Table 3)…”

Myosin Light Chain Phosphatase Plays an Important Role in Cardiac Fibrosis in a Model of Mineralocorticoid Receptor‐Associated Hypertension

“…Transthoracic echocardiography was performed by observers blinded to the groups of the mice using the Vevo 2100 system (FUJIFILM VisualSonics, Toronto, Canada) with a 30‐MHz transducer (MS‐400; FUJIFILM VisualSonics) under 2% isoflurane gas anesthesia to assess cardiac function. 33 Mice were placed in the supine position on a heating pad to maintain body temperature. LV short‐axis cross‐sectional images (papillary muscle level) were visualized in M‐mode.…”

“…LV myocardial cross‐sectional area and cardiac interstitial fibrosis were measured as described elsewhere. 33 Approximately 30 to 40 cells or 15 fields were calculated per heart, then averages were used for analysis. Perivascular fibrosis was evaluated as the ratio of the area of fibrosis surrounding the vessel wall to the total vessel area, according to previous procedures.…”

“…Perivascular fibrosis was evaluated as the ratio of the area of fibrosis surrounding the vessel wall to the total vessel area, according to previous procedures. 20 , 33 …”