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Unraveling New Mechanisms of Renal Fibrosis With Potential Therapeutic Implications

2018; Lippincott Williams & Wilkins; Volume: 72; Issue: 2 Linguagem: Inglês

10.1161/hypertensionaha.118.11043

1524-4563

Francisco Maduell, Núria García-Fernández, Joaquín Manrique, Arantxa González, Javier Dı́ez,

Chronic Kidney Disease and Diabetes

HomeHypertensionVol. 72, No. 2Unraveling New Mechanisms of Renal Fibrosis With Potential Therapeutic Implications Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBUnraveling New Mechanisms of Renal Fibrosis With Potential Therapeutic Implications Francisco Maduell, Nuria Garcia-Fernandez, Joaquín Manrique, Arantxa González and Javier Díez Francisco MaduellFrancisco Maduell From the Division of Nephrology and Renal Transplantation, Hospital Clínic, University of Barcelona, Spain (F.M.) , Nuria Garcia-FernandezNuria Garcia-Fernandez Department of Nephrology (N.G.-F., J.D.) Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain (N.G.-F., J.M., A.G., J.D.). , Joaquín ManriqueJoaquín Manrique University of Navarra Clinic, Pamplona, Spain; Division of Nephrology, Complejo Hospitalario de Navarra, Pamplona, Spain (J.M.) Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain (N.G.-F., J.M., A.G., J.D.). , Arantxa GonzálezArantxa González Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., J.D.) Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain (A.G., J.D.) Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain (N.G.-F., J.M., A.G., J.D.). and Javier DíezJavier Díez Correspondence to Javier Díez, Program of Cardiovascular Diseases, Centre for Applied Medical Research, Ave Pío XII 55, Pamplona, Spain. E-mail E-mail Address: [email protected] Department of Nephrology (N.G.-F., J.D.) Department of Cardiology and Cardiac Surgery (J.D.) Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., J.D.) Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain (A.G., J.D.) Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain (N.G.-F., J.M., A.G., J.D.). Originally published18 Jun 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11043Hypertension. 2018;72:277–278This article is a commentary on the followingSuppression of Endothelial-to-Mesenchymal Transition by SIRT (Sirtuin) 3 Alleviated the Development of Hypertensive Renal InjuryOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 18, 2018: Previous Version of Record See related article, pp 350–360Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminates in tissue fibrosis. When this process progresses for a prolonged period of time, parenchymal scarring and ultimately cellular dysfunction and organ failure ensue. In this conceptual framework, renal fibrosis corresponds to the replacement of renal functional tissue by extracellular matrix proteins, mainly fibrillary collagens, which lead to chronic kidney disease (CKD) and ultimately to chronic kidney failure that represents the end-stage renal disease. The concept of reversing CKD has been intensively researched during the past decade. Indeed, because the prevalence of end-stage renal disease is constantly on the rise, the lack of established antifibrotic therapies is a considerable unmet need in clinical practice. To date, the possibility of effective antifibrotic treatment has been established in experimental models of CKD, and although multiple antifibrotic compounds targeting various components of the fibrotic pathway are being assessed in clinical trials, the available results show that they are ineffective or only slightly successful to prevent or reverse renal fibrosis. Hence, it is essential to understand the pathogenesis of renal fibrosis and to discover and better understand new strategies for treating this lesion from its earliest phases.As in other organs, the mechanistic hallmark of renal fibrosis is the accumulation of a large number of matrix-producing cells or myofibroblasts. These cells are derived from diverse origins, such as resident fibroblasts, vascular pericytes, epithelial-to-mesenchymal transition, and bone marrow (circulating fibrocytes). Recently, endothelial-to-mesenchymal transition (EndoMT) or endothelial-to-myofibroblast transition has been also recognized as a novel mechanism for the generation of myofibroblasts and induction of fibrosis in the kidney.1 Several autocrine or paracrine signaling molecules can induce EndoMT, including the TGF-β (transforming growth factor-β) superfamily of proteins, inflammatory cytokines, vasoactive amines and peptides, and reactive oxygen species.2 On the contrary, several growth factors (eg, vascular endothelial growth factor-A) and some microRNAs (eg, miR-155) appear to be negative regulators of EndoMT.2 Additionally, several pharmacological agents that among other actions inhibit EndoMT (eg, linagliptin, relaxin, cinacalcet, losartan, and spironolactone) have been proposed as potential therapeutic agents to reduce organ fibrosis.2Preliminary data suggest that sirtuins can also regulate EndoMT. Sirtuins comprise a highly conserved family of proteins encoded by the silent information regulator 2 genes. Mammalian SIRT1-7 (sirtuins1-7), also called class III histone deacetylases, are a family of 7 nicotinamide adenine dinucleotide-dependent deacetylases, which perform nonredundant functions in adapting physiology to environmental stressors, namely through chemical reversal of acetyllysine modifications of cellular proteins. Accumulating evidence indicates the beneficial effects of sirtuins, including SIRT1 and SIRT3, in kidney pathophysiology.3 SIRT3 is a nuclear DNA-encoded 44 kDa sirtuin localized in the mitochondrial matrix that acts as a master regulator of mitochondrial function by activating a wide range of targets involved in ATP production, energy metabolism, antioxidant pathway, and mitochondrial dynamics.4Beyond its involvement in maintaining mitochondrial integrity, a growing body of evidence points to SIRT3 as a protective agent against fibrosis developed in response to aging and tissue injury. It has been reported that SIRT3 KO (knockout) mice with age develop fibrosis in the kidney, the heart, and other organs, whereas systemic SIRT3-overexpressing mice do not.5 Of interest, SIRT3 deficiency caused induction of TGF-β expression and signaling in fibrotic organs.5 In the current issue of the journal, Lin et al6 provide a convincing new piece of knowledge on the role of SIRT3 in regulating renal fibrosis through EndoMT for which they deserve to be congratulated. Lin et al6 used the in vivo Ang II (angiotensin II)–induced hypertensive renal injury model, characterized by reduced SIRT3 expression, increase of reactive oxygen species, and activation of EndoMT and fibrosis. In experiments performed in Sirt3 KO mice and in SIRT3 endothelial cell–specific transgenic mice, the authors observed that low SIRT3 exacerbates and high SIRT3 reduces renal reactive oxygen species, EndoMT, fibrosis, and dysfunction induced by chronic Ang II infusion. In addition, the improvement in renal parameters observed in SIRT3 endothelial cell–specific transgenic mice was not associated with changes in blood pressure. Additionally, in in vitro experiments, Lin et al6 found that the ability of Ang II to induce EndoMT and reduce catalase expression in normal mouse glomerular endothelial cells was abrogated in glomerular endothelial cells overexpressing SIRT3. Of interest, SIRT3 overexpression was associated with deacetylation and nuclear localization of Foxo3a and subsequent activation of Foxo3a-dependent catalase expression. Collectively, these findings suggest that SIRT3 may play a protective role against Ang II–induced renal fibrosis and dysfunction through the inhibition of EndoMT (Figure). Furthermore, the authors provide evidence suggesting a role for the activation of Foxo3a-catalase antioxidant pathway as a mechanism potentially involved in the inhibition of EndoMT by SIRT3.Download figureDownload PowerPointFigure. Schematic representation of the involvement of endothelial-to-mesenchymal transition (EndoMT) in the process of renal fibrosis, and the proposed mechanism of action of sirtuin 3 to interfere with this process. Sirtuin 3 may prevent EndoMT by reducing the availability of reactive oxygen species (eg, via activation of the antioxidant enzyme Foxo3a-dependent catalase) or by inhibiting the inflammatory response (eg, via blockade of the TGF-β [transforming growth factor-β]–Smad3 pathway). CKD indicates chronic kidney disease; ECM, extracellular matrix; and RAAS, renin–angiotensin–aldosterone system.The information provided by Lin et al6 sets the stage for the pharmacological activation of SIRT3 to gain advantage of its antifibrotic renal actions. In this regard, it has been reported that honokiol—a natural biphenolic compound that activates SIRT3—blocks cardiac fibroblast proliferation and differentiation to myofibroblasts in a SIRT3-dependent manner7 and reduces cardiac reactive oxygen species and fibrosis in doxorubicin-induced cardiomyopathy in mice.8 In another study, it has been shown that SIRT3 activation induced by the polyphenolic compound resveratrol suppressed Ang II–induced differentiation of cardiac fibroblasts into myofibroblasts through the TGF-β/Smad3 pathway.9 Additional studies are required to test the renal antifibrotic efficacy of these compounds in fibrogenic renal cells and animal models of renal disease.The translational perspective of this approach is given by the observation that SIRT3 protein expression was reduced in peripheral blood mononuclear cells from hypertensive patients compared with normotensive subjects.10 Furthermore, SOD2 (superoxide dismutase 2) acetylation—an inverse index of SIRT3 activity—was higher in cells from hypertensive patients than in cells from normotensive subjects.10 Therefore, it can be hypothesized that the measurement of SIRT3 expression and SOD2 acetylation in peripheral blood mononuclear cells may help to identify patients who may benefit from targeting SIRT3.CKD is a systemic disease, and as such, renal fibrosis is associated with fibrosis in other organs (eg, heart and blood vessels). Furthermore, the process leading to renal fibrosis in CKD shares many features in common with the fibrotic response in other organs. The challenge is, therefore, to find those generic antifibrotic strategies that have potential to ameliorate progression in multiple organs, that is, the overlap. In this conceptual framework, stimulation of SIRT3 emerges as a promising strategy to be tested, namely in patients with CKD with low expression and activity of this protein in peripheral blood mononuclear cells.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Javier Díez, Program of Cardiovascular Diseases, Centre for Applied Medical Research, Ave Pío XII 55, Pamplona, Spain. E-mail [email protected]esReferences1. He JXu YKoya DKanasaki K. Role of the endothelial-to-mesenchymal transition in renal fibrosis of chronic kidney disease.Clin Exp Nephrol. 2013; 17:488–497. doi: 10.1007/s10157-013-0781-0.CrossrefMedlineGoogle Scholar2. Medici D. Endothelial-mesenchymal transition in regenerative medicine.Stem Cells Int. 2016; 2016:6962801. doi: 10.1155/2016/6962801.CrossrefMedlineGoogle Scholar3. Kitada MKume SKoya D. Role of sirtuins in kidney disease.Curr Opin Nephrol Hypertens. 2014; 23:75–79. doi: 10.1097/01.mnh.0000437330.85675.ac.CrossrefMedlineGoogle Scholar4. Perico LMorigi MBenigni A. Mitochondrial sirtuin 3 and renal diseases.Nephron. 2016; 134:14–19. doi: 10.1159/000444370.CrossrefMedlineGoogle Scholar5. Sundaresan NRBindu SPillai VBSamant SPan YHuang JYGupta MNagalingam RSWolfgeher DVerdin EGupta MP. SIRT3 blocks aging-associated tissue fibrosis in mice by deacetylating and activating glycogen synthase kinase 3β.Mol Cell Biol. 2015; 36:678–692. doi: 10.1128/MCB.00586-15.CrossrefMedlineGoogle Scholar6. Lin JZheng YZhang ZShen WLi XWei TRuan CChen XZhu DGao P. Suppression of endothelial-to-mesenchymal transition by SIRT (sirtuin) 3 alleviated the development of hypertensive renal injury.Hypertension. 2018; 72:350–360. doi: 10.1161/HYPERTENSIONAHA.118.10482.LinkGoogle Scholar7. Pillai VBSamant SSundaresan NRRaghuraman HKim GBonner MYArbiser JLWalker DIJones DPGius DGupta MP. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3.Nat Commun. 2015; 6:6656. doi: 10.1038/ncomms7656.CrossrefMedlineGoogle Scholar8. Pillai VBKanwal AFang YHSharp WWSamant SArbiser JGupta MP. Honokiol, an activator of sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice.Oncotarget. 2017; 8:34082–34098. doi: 10.18632/oncotarget.16133.CrossrefMedlineGoogle Scholar9. Chen TLi JLiu JLi NWang SLiu HZeng MZhang YBu P. Activation of SIRT3 by resveratrol ameliorates cardiac fibrosis and improves cardiac function via the TGF-β/Smad3 pathway.Am J Physiol Heart Circ Physiol. 2015; 308:H424–H434. doi: 10.1152/ajpheart.00454.2014.CrossrefMedlineGoogle Scholar10. Dikalova AEItani HANazarewicz RRMcMaster WGFlynn CRUzhachenko RFessel JPGamboa JLHarrison DGDikalov SI. Sirt3 Impairment and SOD2 hyperacetylation in vascular oxidative stress and hypertension.Circ Res. 2017; 121:564–574. doi: 10.1161/CIRCRESAHA.117.310933.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Falkovskaya A, Mordovin V, Pekarskiy S, Ripp T, Zyubanova I, Sitkova E, Lichikaki V, Manukyan M, Suslova T, Gusakova A and Ryabova T (2019) Matrix metalloproteinases in patients with resistant hypertension and type 2 diabetes mellitus: relation with renal blood flow and kidney function, "Arterial'naya Gipertenziya" ("Arterial Hypertension"), 10.18705/1607-419X-2019-25-1-34-45, 25:1, (34-45) Related articlesSuppression of Endothelial-to-Mesenchymal Transition by SIRT (Sirtuin) 3 Alleviated the Development of Hypertensive Renal InjuryJing-rong Lin, et al. Hypertension. 2018;72:350-360 August 2018Vol 72, Issue 2 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.118.11043PMID: 29915017 Originally publishedJune 18, 2018 PDF download Advertisement SubjectsFibrosisHypertensionOxidant Stress