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Emerging strategies to disrupt the central TGF-β axis in kidney fibrosis

  • Michael Rauchman
    Correspondence
    Reprint requests: Michael Rauchman, Division of Nephrology, Washington University School of Medicine, 4950 Children's Place, Box 8126, Saint Louis, MO 63110;
    Affiliations
    Division of Nephrology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri

    VA St. Louis Health Care System, Saint Louis, Missouri
    Search for articles by this author
  • David Griggs
    Affiliations
    Department of Molecular Microbiology and Immunology, Edward A. Doisy Research Center, Saint Louis University, Saint Louis, Missouri
    Search for articles by this author
Published:April 24, 2019DOI:https://doi.org/10.1016/j.trsl.2019.04.003
      Chronic kidney disease (CKD) affects more than 20 million people in the United States and the global burden of this disorder is increasing. Many affected individuals will progress to end stage kidney disease necessitating dialysis or transplantation. CKD is also a major independent contributor to the risk of cardiovascular morbidity and mortality. Tubulointerstitial fibrosis is a final common pathway for most causes of progressive CKD. Currently, there are no clinically available therapies targeting fibrosis that can slow the decline in kidney function. Although it has long been known that TGF-β signaling is a critical mediator of kidney fibrosis, translating this knowledge to the clinic has been challenging. In this review, we highlight some recent insights into the mechanisms of TGF-β signaling that target activation of this cytokine at the site of injury or selectively inhibit pro-fibrotic gene expression. Molecules directed at these targets hold the promise of attaining therapeutic efficacy while limiting toxicity seen with global inhibition of TGF-β. Kidney injury has profound epigenetic effects leading to altered expression of more than a thousand genes. We discuss how drugs targeting epigenetic modifications, some of which are in use for cancer therapy, have the potential to reprogram gene regulatory networks to favor adaptive repair and prevent fibrosis. The lack of reliable biomarkers of kidney fibrosis is a major limitation in designing clinical trials for testing CKD treatments. We conclude by reviewing recent advances in fibrosis biomarker development.

      Abbreviations:

      AKI (acute kidney injury), BET (bromodomina and extra terminal protein), BMP7 (bone morphogenetic protein 7), CKD (chronic kidney disease), DNMT (DNA methyltransferase), ESKD (end stage kidney disease), EZH2 (enhancer of Zeste Homolog), HDAC (histone deacetylase), RAAS (renin angiotensin aldosterone system), Tet (ten-eleven-translocation), TGF (β-transforming growth factor beta), UUO (unilateral ureteral obstruction)
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      References

        • Hoerger T.J.
        • Wittenborn J.S.
        • Segel J.E.
        • et al.
        A health policy model of CKD: 1. Model construction, assumptions, and validation of health consequences.
        Am J Kidney Dis. 2010; 55: 452-462
        • Go A.S.
        • Chertow G.M.
        • Fan D.
        • McCulloch C.E.
        • Hsu C.Y.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351: 1296-1305
        • McCullough K.P.
        • Morgenstern H.
        • Saran R.
        • Herman W.H.
        • Robinson B.M.
        Projecting ESRD incidence and prevalence in the United States through 2030.
        J Am Soc Nephrol. 2019; 30: 127-135
        • Foreman K.J.
        • Marquez N.
        • Dolgert A.
        • et al.
        Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories.
        Lancet. 2018; 392: 2052-2090
        • Chawla L.S.
        • Eggers P.W.
        • Star R.A.
        • Kimmel P.L.
        Acute kidney injury and chronic kidney disease as interconnected syndromes.
        N Engl J Med. 2014; 371: 58-66
        • Sawhney S.
        • Fraser S.D.
        Epidemiology of AKI: utilizing large databases to determine the burden of AKI.
        Adv Chronic Kidney Dis. 2017; 24: 194-204
        • Coca S.G.
        • Singanamala S.
        • Parikh C.R.
        Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.
        Kidney Int. 2012; 81: 442-448
        • Coca S.G.
        Long-term outcomes of acute kidney injury.
        Curr Opin Nephrol Hypertens. 2010; 19: 266-272
        • Basile D.P.
        • Bonventre J.V.
        • Mehta R.
        • et al.
        Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments.
        J Am Soc Nephrol. 2016; 27: 687-697
        • Lee S.Y.
        • Kim S.I.
        • Choi M.E.
        Therapeutic targets for treating fibrotic kidney diseases.
        Transl Res. 2015; 165: 512-530
        • Klahr S.
        • Morrissey J.
        Obstructive nephropathy and renal fibrosis.
        Am J Physiol Renal Physiol. 2002; 283: F861-F875
        • Srivastava A.
        • Palsson R.
        • Kaze A.D.
        • et al.
        The prognostic value of histopathologic lesions in native kidney biopsy specimens: results from the Boston Kidney Biopsy Cohort Study.
        J Am Soc Nephrol. 2018; 29: 2213-2224
        • Breyer M.D.
        • Susztak K.
        The next generation of therapeutics for chronic kidney disease.
        Nat Rev Drug Discov. 2016; 15: 568-588
        • Wilson P.C.
        • Humphreys B.D.
        Single-cell genomics and gene editing: implications for nephrology.
        Nat Rev Nephrol. 2018; 15: 63-64
        • Gewin L.S.
        Renal tubule repair: is Wnt/beta-catenin a friend or foe?.
        Genes (Basel). 2018; 9: E58
        • Bielesz B.
        • Sirin Y.
        • Si H.
        • et al.
        Epithelial notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.
        J Clin Invest. 2010; 120: 4040-4054
        • Yang L.
        • Besschetnova T.Y.
        • Brooks C.R.
        • Shah J.V.
        • Bonventre J.V.
        Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.
        Nat Med. 2010; 16: 535-544
        • Kramann R.
        • Fleig S.V.
        • Schneider R.K.
        • et al.
        Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis.
        J Clin Invest. 2015; 125: 2935-2951
        • Kramann R.
        • Schneider R.K.
        • DiRocco D.P.
        • et al.
        Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.
        Cell Stem Cell. 2015; 16: 51-66
        • Canaud G.
        • Brooks C.R.
        • Kishi S.
        • et al.
        Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair.
        Sci Transl Med. 2019; 11
        • Tang P.M.
        • Nikolic-Paterson D.J.
        • Lan H.Y.
        Macrophages: versatile players in renal inflammation and fibrosis.
        Nat Rev Nephrol. 2019; 15: 144-158
        • Border W.A.
        • Okuda S.
        • Languino L.R.
        • Sporn M.B.
        • Ruoslahti E.
        Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1.
        Nature. 1990; 346: 371-374
        • Sanderson N.
        • Factor V.
        • Nagy P.
        • et al.
        Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.
        Proc Natl Acad Sci U S A. 1995; 92: 2572-2576
        • Kopp J.B.
        • Factor V.M.
        • Mozes M.
        • et al.
        Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease.
        Lab Invest. 1996; 74: 991-1003
        • Border W.A.
        • Noble N.A.
        Evidence that TGF-beta should be a therapeutic target in diabetic nephropathy.
        Kidney Int. 1998; 54: 1390-1391
        • Bitzer M.
        • Sterzel R.B.
        • Bottinger E.P.
        Transforming growth factor-beta in renal disease.
        Kidney Blood Press Res. 1998; 21: 1-12
        • Ju W.
        • Eichinger F.
        • Bitzer M.
        • et al.
        Renal gene and protein expression signatures for prediction of kidney disease progression.
        Am J Pathol. 2009; 174: 2073-2085
        • Duffield J.S.
        Cellular and molecular mechanisms in kidney fibrosis.
        J Clin Invest. 2014; 124: 2299-2306
        • Grande M.T.
        • Sanchez-Laorden B.
        • Lopez-Blau C.
        • et al.
        Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease.
        Nat Med. 2015; 21: 989-997
        • Lovisa S.
        • LeBleu V.S.
        • Tampe B.
        • et al.
        Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis.
        Nat Med. 2015; 21: 998-1009
        • Chung S.
        • Overstreet J.M.
        • Li Y.
        • et al.
        TGF-beta promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration.
        JCI Insight. 2018; 3
        • Kang H.M.
        • Ahn S.H.
        • Choi P.
        • et al.
        Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.
        Nat Med. 2015; 21: 37-46
        • Nishimura S.L.
        Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders.
        Am J Pathol. 2009; 175: 1362-1370
        • Sureshbabu A.
        • Muhsin S.A.
        • Choi M.E.
        TGF-beta signaling in the kidney: pro-fibrotic and protective effects.
        Am J Physiol Renal Physiol. 2016; (Epub Jan 6)
        • Benigni A.
        • Zoja C.
        • Corna D.
        • et al.
        Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat.
        J Am Soc Nephrol. 2003; 14: 1816-1824
        • Gu C.
        • Zhang J.
        • Noble N.A.
        • Peng X.R.
        • Huang Y.
        An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease.
        Am J Physiol Renal Physiol. 2016; 311: F852-Ff63
        • Voelker J.
        • Berg P.H.
        • Sheetz M.
        • et al.
        Anti-TGF-beta1 antibody therapy in patients with diabetic nephropathy.
        J Am Soc Nephrol. 2017; 28: 953-962
        • Mazzucco G.
        • Bertani T.
        • Fortunato M.
        • et al.
        Different patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biopsies.
        Am J Kidney Dis. 2002; 39: 713-720
        • Nlandu-Khodo S.
        • Neelisetty S.
        • Phillips M.
        • et al.
        Blocking TGF-beta and beta-catenin epithelial crosstalk exacerbates CKD.
        J Am Soc Nephrol. 2017; 28: 3490-3503
        • Zeisberg M.
        • Zeisberg E.M.
        Precision renal medicine: a roadmap towards targeted kidney fibrosis therapies.
        Fibrogenesis Tissue Repair. 2015; 8: 16
        • Bouchie A.
        • DeFrancesco L.
        Nature biotechnology's academic spinouts of 2014.
        Nat Biotechnol. 2015; 33: 247-255
        • van Laethem J.L.
        • Deviere J.
        • Resibois A.
        • et al.
        Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis.
        Gastroenterology. 1995; 108: 1873-1881
        • Worthington J.J.
        • Klementowicz J.E.
        • Travis M.A.
        TGFbeta: a sleeping giant awoken by integrins.
        Trends Biochem Sci. 2011; 36: 47-54
        • Henderson N.C.
        • Arnold T.D.
        • Katamura Y.
        • et al.
        Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs.
        Nat Med. 2013; 19: 1617-1624
        • Hynes R.O.
        Integrins: bidirectional, allosteric signaling machines.
        Cell. 2002; 110: 673-687
        • Honda E.
        • Yoshida K.
        • Munakata H.
        Transforming growth factor-beta upregulates the expression of integrin and related proteins in MRC-5 human myofibroblasts.
        Tohoku J Exp Med. 2010; 220: 319-327
        • Zambruno G.
        • Marchisio P.C.
        • Marconi A.
        • et al.
        Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing.
        J Cell Biol. 1995; 129: 853-865
        • Lampi M.C.
        • Reinhart-King C.A.
        Targeting extracellular matrix stiffness to attenuate disease: from molecular mechanisms to clinical trials.
        Sci Transl Med. 2018; 10
        • Santos A.
        • Lagares D.
        Matrix stiffness: the conductor of organ fibrosis.
        Curr Rheumatol Rep. 2018; 20: 2
        • Parker M.W.
        • Rossi D.
        • Peterson M.
        • et al.
        Fibrotic extracellular matrix activates a profibrotic positive feedback loop.
        J Clin Invest. 2014; 124: 1622-1635
        • Zollinger A.J.
        • Smith M.L.
        Fibronectin, the extracellular glue.
        Matrix Biol. 2017; 60-61: 27-37
        • Birukawa N.K.
        • Murase K.
        • Sato Y.
        • et al.
        Activated hepatic stellate cells are dependent on self-collagen, cleaved by membrane type 1 matrix metalloproteinase for their growth.
        J Biol Chem. 2014; 289: 20209-20221
        • Zhou X M.F.
        • Gehdu N.
        • Zhang J.
        • Iredale J.P.
        • Benyon R.C.
        Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells.
        J Biol Chem. 2004; 279 (Epub 2004 Mar 24): 23996-24006
        • Davis G.E.
        • Bayless K.J.
        • Davis M.J.
        • Meininger G.A.
        Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules.
        Am J Pathol. 2000; 156: 1489-1498
        • Fu Y.P.M.
        • Thill M.
        • Yuan P.
        • Wang N.S.
        • Csaky K.G.
        Angiogenesis inhibition and choroidal neovascularization suppression by sustained delivery of an integrin antagonist, EMD478761.
        Invest Ophthalmol Vis Sci. 2007; 48: 5184-5190
        • Pozzi A.
        • Zent R.
        Integrins in kidney disease.
        J Am Soc Nephrol. 2013; 24: 1034-1039
        • Ma L.J.
        • Yang H.
        • Gaspert A.
        • et al.
        Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice.
        Am J Pathol. 2003; 163: 1261-1273
        • Breuss J.M.
        • Gallo J.
        • DeLisser H.M.
        • et al.
        Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling.
        J Cell Sci. 1995; 108: 2241-2251
        • Hahm K.
        • Lukashev M.E.
        • Luo Y.
        • et al.
        Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse.
        Am J Pathol. 2007; 170: 110-125
        • Maile L.A.
        • Busby W.H.
        • Gollahon K.A.
        • et al.
        Blocking ligand occupancy of the alphavbeta3 integrin inhibits the development of nephropathy in diabetic pigs.
        Endocrinology. 2014; 155: 4665-4675
        • Wei C.
        • Moller C.C.
        • Altintas M.M.
        • et al.
        Modification of kidney barrier function by the urokinase receptor.
        Nat Med. 2008; 14: 55-63
        • Chang Y.
        • Lau W.L.
        • Jo H.
        • et al.
        Pharmacologic blockade of alphavbeta1 integrin ameliorates renal failure and fibrosis in vivo.
        J Am Soc Nephrol. 2017; 28: 1998-2005
        • Wilkinson A.L.
        • Barrett J.W.
        • Slack R.J.
        Pharmacological characterisation of a tool alphavbeta1 integrin small molecule RGD-mimetic inhibitor.
        Eur J Pharmacol. 2019; 842: 239-247
        • Babic A.M.
        • Chen C.C.
        • Lau L.F.
        Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo.
        Mol Cell Biol. 1999; 19: 2958-2966
        • Gao R.
        • B D.
        A novel integrin alpha5beta1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells.
        Gut. 2006; 55 (Epub 2005 Dec 16): 856-862
        • McCurley A.
        • Alimperti S.
        • Campos-Bilderback S.B.
        • et al.
        Inhibition of alphavbeta5 integrin attenuates vascular permeability and protects against renal ischemia-reperfusion injury.
        J Am Soc Nephrol. 2017; 28: 1741-1752
        • Ivaska J.
        • Heino J.
        Cooperation between integrins and growth factor receptors in signaling and endocytosis.
        Annu Rev Cell Dev Biol. 2011; 27: 291-320
        • Wickstrom S.A.
        • Fassler R.
        Regulation of membrane traffic by integrin signaling.
        Trends Cell Biol. 2011; 21: 266-273
        • Gao R.
        • Brigstock D.R.
        A novel integrin alpha5beta1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells.
        Gut. 2006; 55: 856-862
        • Khan S.
        • Lakhe-Reddy S.
        • McCarty J.H.
        • et al.
        Mesangial cell integrin alphavbeta8 provides glomerular endothelial cell cytoprotection by sequestering TGF-beta and regulating PECAM-1.
        Am J Pathol. 2011; 178: 609-620
        • Marek I.
        • Lichtneger T.
        • Cordasic N.
        • et al.
        Alpha8 integrin (Itga8) signalling attenuates chronic renal interstitial fibrosis by reducing fibroblast activation, not by interfering with regulation of cell turnover.
        PLoS One. 2016; 11e0150471
        • Murray I.R.
        • Gonzalez Z.N.
        • Baily J.
        • et al.
        Alphav integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis.
        Nat Commun. 2017; 8: 1118
        • Ulmasov B.
        • Neuschwander-Tetri B.A.
        • Lai J.
        • et al.
        Inhibitors of Arg-Gly-Asp-binding integrins reduce development of pancreatic fibrosis in mice.
        Cell Mol Gastroenterol Hepatol. 2016; 2: 499-518
        • Ley K.
        • Rivera-Nieves J.
        • Sandborn W.J.
        • Shattil S.
        Integrin-based therapeutics: biological basis, clinical use and new drugs.
        Nat Rev Drug Discov. 2016; 15: 173-183
        • Cirkel G.A.
        • Kerklaan B.M.
        • Vanhoutte F.
        • et al.
        A dose escalating phase I study of GLPG0187, a broad spectrum integrin receptor antagonist, in adult patients with progressive high-grade glioma and other advanced solid malignancies.
        Invest New Drugs. 2016; (Epub Jan 20)
        • Hariharan S.
        • Gustafson D.
        • Holden S.
        • et al.
        Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors.
        Ann Oncol. 2007; 18: 1400-1407
        • O'Day S.
        • Pavlick A.
        • Loquai C.
        • et al.
        A randomised, phase II study of intetumumab, an anti-[alpha]v-integrin mAb, alone and with dacarbazine in stage IV melanoma.
        Br J Cancer. 2011; 105: 346-352
        • Ricart A.D.
        • Tolcher A.W.
        • Liu G.
        • et al.
        Volociximab, a chimeric monoclonal antibody that specifically binds α5β1 integrin: a phase I, pharmacokinetic, and biological correlative study.
        Clin Cancer Res. 2008; 14: 7924-7929
        • Murphy P.A.
        • Begum S.
        • Hynes R.O.
        Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors.
        PLoS One. 2015; 10e0120872
        • Reynolds A.R.
        • Reynolds L.E.
        • Nagel T.E.
        • et al.
        Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice.
        Cancer Res. 2004; 64: 8643-8650
        • Reynolds AR H.I.
        • Watson A.R.
        • Welti J.C.
        • et al.
        Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.
        Nat Med. 2009; 15 (Epub 2009 Mar 22): 392-400
        • Ichinose K.
        • Maeshima Y.
        • Yamamoto Y.
        • et al.
        Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model.
        Diabetes. 2005; 54: 2891-2903
        • Masuda K.
        • Tanabe K.
        • Ujike H.
        • et al.
        Deletion of pro-angiogenic factor vasohibin-2 ameliorates glomerular alterations in a mouse diabetic nephropathy model.
        PLoS One. 2018; 13e0195779
        • Tanabe K.
        • Maeshima Y.
        • Sato Y.
        • Wada J.
        Antiangiogenic therapy for diabetic nephropathy.
        Biomed Res Int. 2017; 20175724069
        • Sun Y.
        • Zhang Y.
        • Chi P.
        Pirfenidone suppresses TGFbeta1induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the SMAD and PI3K/AKT signaling pathway.
        Mol Med Rep. 2018; 18: 3907-3913
        • Xu M.Y.
        • Porte J.
        • Knox A.J.
        • et al.
        Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q).
        Am J Pathol. 2009; 174: 1264-1279
        • Wu T.
        • Kooi C.V.
        • Shah P.
        • et al.
        Integrin-mediated cell surface recruitment of autotaxin promotes persistent directional cell migration.
        Faseb J. 2014; 28: 861-870
        • Zeisberg M.
        • Hanai J.
        • Sugimoto H.
        • et al.
        BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.
        Nat Med. 2003; 9: 964-968
        • Sugimoto H.
        • LeBleu V.S.
        • Bosukonda D.
        • et al.
        Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis.
        Nat Med. 2012; 18: 396-404
        • Soofi A.
        • Zhang P.
        • Dressler G.R.
        Kielin/chordin-like protein attenuates both acute and chronic renal injury.
        J Am Soc Nephrol. 2013; 24: 897-905
        • Bradford S.T.J.
        • Ranghini E.J.
        • Grimley E.
        • Lee P.H.
        • Dressler G.R.
        High-throughput screens for agonists of bone morphogenetic protein (BMP) signaling identify potent benzoxazole compounds.
        J Biol Chem. 2019; 294: 3125-3136
        • Palumbo-Zerr K.
        • Zerr P.
        • Distler A.
        • et al.
        Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis.
        Nat Med. 2015; 21: 150-158
        • Pherson M.
        • Misulovin Z.
        • Gause M.
        • et al.
        Polycomb repressive complex 1 modifies transcription of active genes.
        Sci Adv. 2017; 3e1700944
        • Rickels R.
        • Herz H.M.
        • Sze C.C.
        • et al.
        Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability.
        Nat Genet. 2017; 49: 1647-1653
        • Oba S.
        • Ayuzawa N.
        • Nishimoto M.
        • et al.
        Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells.
        Sci Rep. 2018; 8: 16338
        • Bechtel W.
        • McGoohan S.
        • Zeisberg E.M.
        • et al.
        Methylation determines fibroblast activation and fibrogenesis in the kidney.
        Nat Med. 2010; 16: 544-550
        • Tampe B.
        • Steinle U.
        • Tampe D.
        • et al.
        Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression.
        Kidney Int. 2017; 91: 157-176
        • Tampe B.
        • Tampe D.
        • Muller C.A.
        • et al.
        Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis.
        J Am Soc Nephrol. 2014; 25: 905-912
        • Tampe B.
        • Tampe D.
        • Zeisberg E.M.
        • et al.
        Induction of Tet3-dependent epigenetic remodeling by low-dose hydralazine attenuates progression of chronic kidney disease.
        EBioMedicine. 2015; 2: 19-36
        • Xu X.
        • Tan X.
        • Tampe B.
        • et al.
        High-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis.
        Nat Commun. 2018; 9: 3509
        • Tan X.
        • Xu X.
        • Zeisberg E.M.
        • Zeisberg M.
        High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation.
        Biochem Biophys Res Commun. 2016; 472: 459-464
        • Heylen L.
        • Thienpont B.
        • Naesens M.
        • et al.
        Ischemia-induced DNA hypermethylation during kidney transplant predicts chronic allograft injury.
        J Am Soc Nephrol. 2018; 29: 1566-1576
        • Wing M.R.
        • Devaney J.M.
        • Joffe M.M.
        • et al.
        DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC study.
        Nephrol Dial Transplant. 2014; 29: 864-872
        • Ko Y.A.
        • Mohtat D.
        • Suzuki M.
        • et al.
        Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development.
        Genome Biol. 2013; 14: R108
        • Qiu C.
        • Huang S.
        • Park J.
        • et al.
        Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease.
        Nat Med. 2018; 24: 1721-1731
        • Advani A.
        • Huang Q.
        • Thai K.
        • et al.
        Long-term administration of the histone deacetylase inhibitor vorinostat attenuates renal injury in experimental diabetes through an endothelial nitric oxide synthase-dependent mechanism.
        Am J Pathol. 2011; 178: 2205-2214
        • Choi H.S.
        • Song J.H.
        • Kim I.J.
        • et al.
        Histone deacetylase inhibitor, CG200745 attenuates renal fibrosis in obstructive kidney disease.
        Sci Rep. 2018; 8: 11546
        • Mishra N.
        • Reilly C.M.
        • Brown D.R.
        • Ruiz P.
        • Gilkeson G.S.
        Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse.
        J Clin Invest. 2003; 111: 539-552
        • Novitskaya T.
        • McDermott L.
        • Zhang K.X.
        • et al.
        A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury.
        Am J Physiol Renal Physiol. 2014; 306: F496-F504
        • Liu N.
        • He S.
        • Ma L.
        • et al.
        Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling.
        PLoS One. 2013; 8: e54001
        • Hukriede N.
        • Vogt A.
        • de Caestecker M.
        Drug discovery to halt the progression of acute kidney injury to chronic kidney disease: a case for phenotypic drug discovery in acute kidney injury.
        Nephron. 2017; 137: 268-272
        • Skrypnyk N.I.
        • Sanker S.
        • Brilli-Skvarca L.
        • et al.
        Delayed treatment with PTBA analogs reduces post injury renal fibrosis after kidney injury.
        Am J Physiol Renal Physiol. 2015; (Epub Dec 9)
        • Zhou X.
        • Zang X.
        • Ponnusamy M.
        • et al.
        Enhancer of Zeste Homolog 2 inhibition attenuates renal fibrosis by maintaining SMAD7 and phosphatase and tensin homolog expression.
        J Am Soc Nephrol. 2016; 27: 2092-2108
        • Suarez-Alvarez B.
        • Morgado-Pascual J.L.
        • Rayego-Mateos S.
        • et al.
        Inhibition of bromodomain and extraterminal domain family proteins ameliorates experimental renal damage.
        J Am Soc Nephrol. 2017; 28: 504-519
        • Zhou B.
        • Mu J.
        • Gong Y.
        • et al.
        Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-beta-mediated Nox4 expression.
        Redox Biol. 2017; 11: 390-402
        • Wang P.
        • Luo M.L.
        • Song E.
        • et al.
        Long noncoding RNA lnc-TSI inhibits renal fibrogenesis by negatively regulating the TGF-beta/Smad3 pathway.
        Sci Transl Med. 2018; 10
        • Gomez I.G.
        • MacKenna D.A.
        • Johnson B.G.
        • et al.
        Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways.
        J Clin Invest. 2015; 125: 141-156
        • Blokhin I.
        • Khorkova O.
        • Hsiao J.
        • Wahlestedt C.
        Developments in lncRNA drug discovery: where are we heading?.
        Expert Opin Drug Discov. 2018; 13: 837-849
        • Mansour S.G.
        • Puthumana J.
        • Coca S.G.
        • Gentry M.
        • Parikh C.R.
        Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review.
        BMC Nephrol. 2017; 18: 72
        • Craciun F.L.
        • Bijol V.
        • Ajay A.K.
        • et al.
        RNA sequencing identifies novel translational biomarkers of kidney fibrosis.
        J Am Soc Nephrol. 2016; 27: 1702-1713
        • Barratt J.
        • Topham P.
        Urine proteomics: the present and future of measuring urinary protein components in disease.
        Can Med Assoc J. 2007; 177: 361-368
        • Genovese F.
        • Manresa A.A.
        • Leeming D.J.
        • Karsdal M.A.
        • Boor P.
        The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?.
        Fibrogenesis Tissue Repair. 2014; 7: 4
        • Klein J.
        • Bascands J.L.
        • Mischak H.
        • Schanstra J.P.
        The role of urinary peptidomics in kidney disease research.
        Kidney Int. 2016; 89: 539-545
        • Magalhaes P.
        • Pejchinovski M.
        • Markoska K.
        • et al.
        Association of kidney fibrosis with urinary peptides: a path towards non-invasive liquid biopsies?.
        Sci Rep. 2017; 7: 16915
        • Papasotiriou M.
        • Genovese F.
        • Klinkhammer B.M.
        • et al.
        Serum and urine markers of collagen degradation reflect renal fibrosis in experimental kidney diseases.
        Nephrol Dial Transplant. 2015; 30: 1112-1121
        • Fenton A.
        • Jesky M.D.
        • Ferro C.J.
        • et al.
        Serum endotrophin, a type VI collagen cleavage product, is associated with increased mortality in chronic kidney disease.
        PLoS One. 2017; 12e0175200
        • Rasmussen D.G.K.
        • Fenton A.
        • Jesky M.
        • et al.
        Urinary endotrophin predicts disease progression in patients with chronic kidney disease.
        Sci Rep. 2017; 7: 17328
        • Nielsen M.J.
        • Veidal S.S.
        • Karsdal M.A.
        • et al.
        Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C.
        Liver Int. 2015; 35: 429-437
        • Rasmussen D.G.K.
        • Hansen T.W.
        • von Scholten B.J.
        • et al.
        Higher collagen VI formation is associated with all-cause mortality in patients with type 2 diabetes and microalbuminuria.
        Diabetes Care. 2018; 41: 1493-1500
        • Gholaminejad A.
        • Abdul Tehrani H.
        • Gholami Fesharaki M.
        Identification of candidate microRNA biomarkers in renal fibrosis: a meta-analysis of profiling studies.
        Biomarkers. 2018; 23: 713-724
        • Kirpalani A.
        • Hashim E.
        • Leung G.
        • et al.
        Magnetic resonance elastography to assess fibrosis in kidney allografts.
        Clin J Am Soc Nephrol. 2017; 12: 1671-1679
        • Leung G.
        • Kirpalani A.
        • Szeto S.G.
        • et al.
        Could MRI be used to image kidney fibrosis? A review of recent advances and remaining barriers.
        Clin J Am Soc Nephrol. 2017; 12: 1019-1028
        • Lin H.Y.
        • Lee Y.L.
        • Lin K.D.
        • et al.
        Association of renal elasticity and renal function progression in patients with chronic kidney disease evaluated by real-time ultrasound elastography.
        Sci Rep. 2017; 7: 43303
        • Morrell G.R.
        • Zhang J.L.
        • Lee V.S.
        Magnetic resonance imaging of the fibrotic kidney.
        J Am Soc Nephrol. 2017; 28: 2564-2570