Abstract
The aim of this study was to assess any potential additive effects of a treatment combining aliskiren with paricalcitol on reducing renal fibrosis. C57BL/6J mice were treated individually with aliskiren and/or paricalcitol until 7 days after initiation of unilateral ureteral obstruction (UUO).In obstructed kidneys of UUO mice, monotherapy with aliskiren or paricalcitol significantly attenuated interstitial fibrosis, collagen IV accumulation, and α-smooth muscle actin- and terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling-positive cells. The combination treatment showed additive efficacy in inhibition of these parameters. Renal NADPH oxidase (Nox)1 and Nox2 were significantly decreased by aliskiren or paricalcitol alone or in combination, while renal Nox4 expression was significantly reduced by paricalcitol mono- or combination treatment. Increased levels of p-Erk and p-p38 MAPK, and NF-κB in UUO kidneys were also significantly reduced by either aliskiren or paricalcitol treatment alone or in combination. Aliskiren or paricalcitol monotherapy significantly reduced the expression of (pro)renin receptor in UUO kidneys. In addition, aliskiren tended to augment renin expression in UUO kidneys, but paricalcitol reduced its expression level. The combination treatment effectively blocked both (pro)renin receptor and renin expression induced by aliskiren, and resulted in a further reduction of the renal expression of angiotensin II AT1 receptor. Aliskiren failed to increase the expression of vitamin D receptor in UUO kidneys, but the combination treatment restored its expression level. Taken together, a treatment combining aliskiren with paricalcitol better inhibits UUO-induced renal injury. The mechanism of this synergy may involve more profound inhibition of the intrarenal renin-angiotensin system.
Highlights
Renin is synthesized by the juxtaglomerular cells of the renal afferent arterioles as preprorenin [1]
This study investigated the possible role of this combined treatment in ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis
MO, USA) as a vehicle; (3) UUO group (UUO+A; n = 8) treated with aliskiren 20 mg/kg/day via a mini-osmotic pump (Alzet Osmotic Pumps, Cupertino, CA, USA); (4) UUO group (UUO+P; n = 8) treated by daily intraperitoneal injection of paricalcitol (Abbott, IL, USA) at a dose of 0.3 μg/kg/day; and (5) UUO group (UUO+A+P; n = 8) treated with both aliskiren and paricalcitol
Summary
Renin is synthesized by the juxtaglomerular cells of the renal afferent arterioles as preprorenin [1]. Cleavage of a 23 amino acid peptide at the carboxyl terminus of preprorenin generates prorenin, which is converted to active renin by proteolytic cleavage of the 43-amino acid N-terminal prosegment [1,2]. Renin acts in the rate-limiting step to cleave angiotensinogen synthesized by the liver, forming angiotensin I [3,4]. Renin is positioned at the top of the renin-angiotensin system (RAS) that preserves end-organ perfusion by regulating extracellular fluid, sodium and water balance, and cardiovascular activity [4,5]. In various renal injury models, the activation of the RAS increases transforming growth factorbeta (TGF-β), plasminogen activator inhibitor (PAI)-1 and α-smooth muscle actin (α-SMA) expressions in the kidneys [1, 6], contributing to the progression of renal interstitial fibrosis
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