The Synergistic Effect of Mizoribine and a Direct Renin Inhibitor, Aliskiren, on Unilateral Ureteral Obstruction Induced Renal Fibrosis in Rats

Sakuraya, Koji; Endo, Amane; Someya, Tomonosuke; Hirano, Daishi; Murano, Yayoi; Fujinaga, Shuichiro; Ohtomo, Yoshiyuki; Shimizu, Toshiaki

doi:10.1016/j.juro.2013.10.053

Cited by 14 publications

(15 citation statements)

References 28 publications

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“…Interestingly, aliskiren significantly inhibited mRNA expression of these proinflammatory cytokines. In one other study (42), aliskiren also reduced MCP-1 mRNA levels in UUO in the obstructed kidney. The effect of aliskiren on cytokine levels, as observed from the present study, indicated its persistently protective action as an anti-inflammatory agent, which improves the inflammatory response and ameliorates the compromised tubular function that is associated with UUO.…”

Section: Discussionmentioning

confidence: 78%

“…In addition, aliskiren has been shown to protect kidneys from acute kidney injuries induced by either contrast (23) or ischemia-reperfusion (17,50) or by chronic kidney diseases (e.g., in diabetic nephropathy) (22,49) as well as by doxorubicin-induced nephrotoxicity (39). Aliskiren alone or in combination with other drugs has also been shown to attenuate renal fibrosis and inflammation induced by ureteral obstruction (8,42,52).…”

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confidence: 99%

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Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

Wang

Luo

Lin

et al. 2015

American Journal of Physiology-Renal Physiology

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Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-β and tumor necrosis factor-α, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction.

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

Wang

Luo

Lin

et al. 2015

American Journal of Physiology-Renal Physiology

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“…Aliskiren is an oral direct renin inhibitor that has been introduced to treat hypertension [ 6 ]. Subsequently, independent of blood pressure control, aliskiren alone or in combination with other drugs has been shown to attenuate renal fibrosis and inflammation induced by unilateral ureteral obstruction (UUO) [ 6 , 13 ]. In a mouse model of UUO, aliskiren decreased the increased levels of inflammatory markers such as renal CD68-positive cells, monocyte chemotactic protein (MCP)-1 and osteopontin mRNA levels in obstructed kidneys [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Treatment combining aliskiren with paricalcitol is effective against progressive renal tubulointerstitial fibrosis via dual blockade of intrarenal renin

Chung

Kim

et al. 2017

PLoS ONE

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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.

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“…TGF‐β1 plays fundamental roles in the following processes: modulation of cell growth, maturation and differentiation, the formation of ECM, homeostasis, plasticity of endothelial cells, immune regulation, apoptosis, angiogenesis and cancer progression (Heldin, Landström, & Moustakas, ; Ikushima & Miyazono, ; Moses & Barcellos‐Hoff, ; Parvani, Taylor, & Schiemann, ; Van Meeteren & Ten Dijke, ). Its reduction in cardiac, renal, hepatic, lung and peritoneal tissues and in diabetic animals treated with the drug is a beneficial effect (Aihara et al, ; Asker et al, ; Bae et al, ; Baracho et al, ; Choi et al, ; Elrashidy, Asker, & Mohamed, ; Gross et al, ; Kavvadas et al, ; Ke et al, ; Kishina et al, ; Lee, Chan, Hsieh, Huang, & Lin, ; Lizakowski et al, ; Sakuraya et al, ; Sun et al, ; Wang et al, ; Weng et al, ; Wu et al, ; Yamada et al, ; Zhao et al, ; Zhou, Liu, Cheung, & Huang, ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the drug reduced MCP‐1 concentrations in diabetic models (Furukawa et al, ; Kishina et al, ; Sakuraya et al, ; Satoh et al, ). MCP‐1 attracts monocytes to inflammatory sites of the vascular subendothelial space, initiating the migration of these cells into the arterial wall and leading to the formation of foam cells.…”

Section: Discussionmentioning

confidence: 99%

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review

Marin

Bertassoli²,

Carvalho

et al. 2019

Drug Development Research

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Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty‐three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.

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The Synergistic Effect of Mizoribine and a Direct Renin Inhibitor, Aliskiren, on Unilateral Ureteral Obstruction Induced Renal Fibrosis in Rats

Abstract: Aliskiren and mizoribine combination therapy provides increased renal protection against renal fibrosis and unilateral ureteral obstruction induced inflammation.

Cited by 14 publications

References 28 publications

Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

Treatment combining aliskiren with paricalcitol is effective against progressive renal tubulointerstitial fibrosis via dual blockade of intrarenal renin

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review

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