RESEARCH ARTICLE The use of aliskiren as an antifibrotic drug in experimental models: A systematic review Thainá Altarejo Marin 1 | Bruno Machado Bertassoli 2 | Alzira Alves de Siqueira de Carvalho 3 | David Feder 1 1 Department of Phamacology, Faculdade de Medicina do ABC, Santo André, SP, Brazil 2 Department of Biology, UFMG, Belo Horizonte, MG, Brazil 3 Department of Neurology, Faculdade de Medicina do ABC, Santo André, SP, Brazil Correspondence Thainá Altarejo Marin, Pharmacology Department, Centro Universitário Saúde ABC, Avenida Lauro Gomes, 2000, Santo André SP, Brazil. Email: thaina.marin@hotmail.com Abstract Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling path- way of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this system- atic 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 ana- lyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cyto- kines, 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 albu- min/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 depo- sition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many stud- ies 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 pathophysio- logical role is suggested. KEYWORDS aliskiren, antifibrotic drug, fibrogenic cytokine, fibrosis, renin-angiotensin-aldosterone system Abbreviations: ACEIs, ACE inhibitor; ACR, Albumin creatinine relation; Akt, Kinase protein; AMPK, 5 0 Adenosine monophosphate-activated protein kinase; Ang II, Angiotensin II; ANP, Atrial natriuretic peptide; ARB, Angiotensin receptor blocker; BP, Blood pressure; COL1α1, Collagen type1 α1; COX-2, Cyclooxygenase -2; CTGF, Connective tissue growing factor; DNMT1, DNA Methyltransferase 1; ECM, Extracellular membrane; ERK, Extracellular signal-regulated protein kinase; GPX1, Glutathione peroxidase; 4-HNE, Hydroxynonenal; IFN, Interferon; iNOS, Inducible nitric oxide synthase; MCP-1, Monocyte chemoattractant protein-1; MEK1, Mitogen-activated protein kinase; MHC, Major histocompatibility complex; MMP, Metalloproteinase; NADP, Nicotinamide adenine dinucleotide phosphate; OPN, Osteopontin; PAI-1, Plasminogen activator inhibitor-1; PPARα, Peroxisome proliferator-activated receptor α; (P)RR, Pro-renin receptor; RAAS, Renin angiotensin aldosterone system; p-SAPK/JNK, Stress-activated protein kinase/Jun-amino-terminal kinase; α-SMA, α-Smooth muscle actin; SMAD, Small mother against decapentaplegic; SOD, Superoxide dismutase; TBARS, Thiobarbituric acid reactive substances; TGF-β1, Transforming growth factor-β1; TIMPs, Tissue inhibitor of metalloproteinase; TLR4, Toll-like receptor; TNF-α, Tumor necrosis factor-α; VEGF, Vascular endothelial growth factor. Received: 11 July 2019 Revised: 21 August 2019 Accepted: 13 September 2019 DOI: 10.1002/ddr.21610 Drug Dev Res. 2019;1–13. wileyonlinelibrary.com/journal/ddr © 2019 Wiley Periodicals, Inc. 1