Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

Abstract

Angiotensin receptor blockers (ARBs) or T-and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg À1 ), efonidipine (30 mg kg À1 ), irbesartan (60 mg kg À1 )+efonidipine (30 mg kg À1 ), amlodipine (3 mg kg À1 ), or irbesartan (60 mg kg À1 )+amlodipine (3 mg kg À1 ) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine-and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22 phox , transforming growth factor-b, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T-and L-type CCB might produce a powerful renal protective effect. INTRODUCTIONKidneys have an important role not only in the homeostasis of water and electrolyte balance but also in the regulation of blood pressure. Angiotensin II is a crucial peptide for regulating blood pressure by slow and rapid pressor responses. The main functions of slow response are augmentation of sodium reabsorption in the proximal tubules and release of aldosterone from the adrenal cortex, whereas the main functions of rapid response are direct contractile response in peripheral resistance arteries and enhancement of peripheral noradrenergic neurotransmission. Therefore, blockade of angiotensin II is a useful antihypertensive strategy. In addition, angiotensin II directly increases mesangial matrix formation by stimulating transforming growth factor (TGF)-b expression. 1 Inhibition of angiotensin II function induces dilation of efferent arterioles, and this mechanism contributes to amelioration of glomerular hypertension, resulting in a decrease in mesangial matrix formation. 2 Therefore, blockade of angiotensin II is also useful for preventing glomerular injury.Calcium channel blockers (CCBs), such as angi...

The phosphodiesterase 5 inhibitor tadalafil has renoprotective effects in a rat model of chronic kidney disease

“…*p < .05 and **p < .01 vs. NS to hypertension and are considered renoprotective for the amelioration of glomerular hyperfiltration. However, some of these agents are ineffective in improving proteinuria even with a reduction in BP (Takai et al, 2010;Yao et al, 2003). In this study, tadalafil attenuated proteinuria, SCr levels, and kidney tissue injuries such as fibrosis and glomerulosclerosis, similar to other antihypertensive agents; even low-dose tadalafil displayed significant renoprotective effects while exhibiting no significant BP-lowering activity.…”

“…However, these treatments have little effect on reducing ESKD. Moreover, the calcium channel blocker, amlodipine, prevents BP elevation but not proteinuria and kidney injury in a salt-sensitive model of hypertension (Takai, Jin, Sakonjo, & Miyazaki, 2010).…”

Transplantation of mesenchymal stem cells into the renal medulla attenuated salt-sensitive hypertension in Dahl S rat

“…MCP-1 is one of the key chemokines that increases monocyte infiltration into inflamed tissues and an important inflammatory mediator [25]. Increased MCP-1 levels in the kidneys have been associated with renal inflammation and hypertension [26–28]. We then used IL-1β and MCP-1 to represent proinflammatory factors in the renal medulla.…”

Off the Beaten Renin–Angiotensin–Aldosterone System Pathway: New Perspectives on Antiproteinuric Therapy

“…46 Furthermore, dihydropyridine calcium channel blockers also antagonize aldosterone-mediated activation of the mineralocorticoid receptor, and efonidipine reduces plasma aldosterone concentrations and glomerular injury in Dahl salt-sensitive rats. 47,48 …”