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Objectives: The present study was undertaken to examine the role of endothelial nitric oxide synthase (eNOS) in salt-sensitive renal injury., Methods: The effects of high-salt diet on renal injury were compared between wild-type and eNOS-/- mice. To examine the role of glomerular angiotensin II and oxidative stress, high-salt fed eNOS-/- mice were given irbesartan, an angiotensin receptor blocker, or tempol, an antioxidant., Results: Four weeks of high-salt diet in wild-type mice, which rapidly caused glomerular eNOS activation and subsequent increase in nitric oxide, did not at all induce renal injury, indicating that wild-type mice are salt-resistant. On the contrary, high-salt diet in eNOS-/- mice, which little increased nitric oxide, rapidly increased urinary albumin excretion, followed by glomerular macrophage infiltration and glomerular sclerosis. Thus, eNOS deficiency caused salt-sensitive glomerular injury. Salt-induced glomerular injury in eNOS-/- mice was preceded by rapid enhancement of glomerular superoxide followed by enhancement of glomerular endothelial angiotensinogen and angiotensin II. Irbesartan and tempol, independently of blood pressure, markedly prevented salt-induced glomerular injury in eNOS-/- mice, and these protective effects were attributed to the attenuation of glomerular oxidative stress and glomerular angiotensinogen-derived angiotensin II., Conclusion: We propose that eNOS dysfunction plays a causative role in salt-induced glomerular injury, through augmentation of glomerular oxidative stress-induced angiotensinogen.

Objectives: High-salt diet is closely associated with the increase in cardiovascular events. However, the mechanism of high-salt-induced cardiovascular injury is unknown. The present study was undertaken to test our hypothesis that apoptosis signal-regulating kinase (ASK) 1 may be involved in salt-induced cardiovascular injury., Methods: Wild-type and ASK1-/- mice were fed a low-salt or a high-salt diet for 10 weeks and the effects of high-salt diet on food intake, urinary volume and electrolyte excretion, and cardiovascular injury were compared between both groups of mice., Results: High-salt diet in wild-type and ASK1-/- mice similarly increased food intake, water intake, urine volume, and urinary sodium excretion, and comparably decreased plasma renin activity and aldosterone. Thus, ASK1 appears to play a minor role in the increase in natriuresis and the decrease in plasma renin, and aldosterone caused by high-salt diet. High-salt diet enhanced the phosphorylation of cardiovascular ASK1 in wild-type mice. High-salt diet in wild-type mice enhanced cardiac transforming growth factor-β1, interstitial fibrosis, coronary perivascular fibrosis, and inflammatory cell infiltration, and these changes were associated with the increase in cardiac superoxide and Nox2. ASK1 deficiency abolished the above-mentioned high-salt-induced cardiac injury. High-salt diet also caused the impairment of vascular endothelium-dependent relaxation by acetylcholine and increased vascular superoxide, and Nox2 in wild-type mice, whereas it did not cause vascular injury in ASK1-/- mice., Conclusion: ASK1 is implicated in cardiac inflammation and fibrosis, and vascular endothelial dysfunction caused by high-salt diet, through the enhancement of oxidative stress.

Objectives: Addition of aliskiren, a direct renin inhibitor, to losartan provides additive reduction of urinary albumin excretion in type 2 diabetic patients. However, the detailed effect of aliskiren on type 2 diabetic nephropathy is still unknown. This study was undertaken to examine the efficacy of aliskiren and the combination of aliskiren with valsartan on type 2 diabetic nephropathy., Methods: db/db mice were treated with aliskiren (3 mg/kg per day), valsartan (5 or 10 mg/kg per day), combined aliskiren (3 mg/kg per day) and valsartan (5 mg/kg per day), and hydralazine (80 mg/kg per day), for 6 weeks, and the protective effects against diabetic nephropathy were compared among each group., Results: Aliskiren significantly attenuated albuminuria and glomerular mesangial matrix expansion in db/db mice, which was associated with the improvement of the increased glomerular transforming growth factor-beta and type IV collagen expressions, the increased macrophage infiltration, and the decreased glomerular nephrin expression of db/db mice. These protective effects of aliskiren in db/db mice were attributed to the attenuation of p22(phox)-related nicotinamide adenine dinucleotide phosphate oxidase-induced superoxide. Addition of aliskiren to valsartan treatment provided more beneficial effects on all the above-mentioned parameters than valsartan monotherapy., Conclusion: Aliskiren protected against type 2 diabetic nephropathy, through pleiotropic effects, and significantly enhanced the protective effects of valsartan against diabetic nephropathy in db/db mice.

Objectives: Benidipine is a dihydropyridine calcium channel blocker inhibiting not only L-type but also T-type calcium channels. To elucidate potential additive benefit of benidipine for prevention of cardiorenal injury, we compared the cardiac and renal protective effects of equihypotensive doses of benidipine and cilnidipine in stroke-prone spontaneously hypertensive rats (SHRSP)., Methods: SHRSP were divided into five groups, and were given vehicle, benidipine at 1 or 3 mg/kg per day, or cilnidipine at 1 or 3 mg/kg per day for 7 weeks, and the protective effects against cardiorenal injury were compared among each group., Results: Benidipine and cilnidipine at the same doses exerted comparable hypotensive effects on SHRSP throughout the treatment. Despite equihypotensive effects between both drugs, benidipine prevented cardiac hypertrophy, fibrosis, and inflammation to a greater extent than cilnidipine. Moreover, benidipine prevented glomerulosclerosis, tubulointerstitial injury, and renal inflammation more than cilnidipine. To elucidate the underlying mechanism of more beneficial effects of benidipine than cilnidipine, we compared the effects of these drugs on cardiac and renal oxidative stress, and aldosterone in SHRSP. Benidipine reduced both cardiac and renal NADPH oxidase activities in SHRSP more than cilnidipine, being associated with more attenuation of cardiac and renal superoxide by benidipine. Furthermore, serum aldosterone was significantly reduced by benidipine but not by cilnidipine., Conclusion: Benidipine exerted more protective effects against cardiorenal injury of hypertensive rats than cilnidipine, through more attenuation of oxidative stress than cilnidipine, and the reduction of aldosterone. Benidipine, via blockade of T-type calcium channels, seems to elicit additive benefits for prevention of hypertensive cardiorenal injury.

Objectives: The efficacy of renin-angiotensin system (RAS) blockers on type 2 diabetes and its complications remains to be defined. This study was undertaken to test the hypothesis that candesartan may enhance the protective effects of pioglitazone against type 2 diabetes., Methods: We compared the effects of pioglitazone, candesartan, and their combination on cardiorenal and vascular injury, diabetes, and tissue oxidative stress in obese and type 2 diabetic db/db mice, and also examined the effects of tempol, a superoxide dismutase (SOD) mimetic, on db/db mice to define the role of oxidative stress., Results: The addition of candesartan to pioglitazone significantly potentiated the suppressive effects of pioglitazone on cardiac macrophage infiltration and interstitial fibrosis, and glomerular macrophage infiltration and sclerosis in db/db mice. These benefits of the combination of pioglitazone and candesartan in db/db mice were attributed to additive attenuation of cardiorenal oxidative stress, through the attenuation of NADPH oxidase or the restoration of Cu/Zn-SOD and EC-SOD. The combination of these drugs reversed vascular endothelial dysfunction in db/db mice more than either monotherapy, by causing more phosphorylation of eNOS. Candesartan slightly augmented the improvement of glucose tolerance by pioglitazone in db/db mice, and this additive effect was mediated by more attenuation of oxidative stress., Conclusions: Our work demonstrated that candesartan significantly potentiated the protective effects of pioglitazone against cardiorenal and vascular injury, and diabetes in obese type 2 diabetic mice. Thus, the combination of pioglitazone with candesartan is potentially a promising therapeutic strategy for type 2 diabetes.