Abstract
Renal fibrosis is the common pathway for progression of chronic kidney disease (CKD) to end stage of renal disease. It is now widely accepted that the degree of renal fibrosis correlates with kidney function and CKD stages. The key cellular basis of renal fibrosis includes activation of myofibroblasts, excessive production of extracellular matrix components, and infiltration of inflammatory cells. Many cellular mechanisms responsible for renal fibrosis have been identified, and some antifibrotic agents show a greater promise in slowing down and even reversing fibrosis in animal models; however, translating basic findings into effective antifibrotic therapies in human has been limited. In this chapter, we will discuss the effects and mechanisms of some novel antifibrotic agents in both preclinical studies and clinical trials.
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Adler SG, Schwartz S, Williams ME, Arauz-Pacheco C, Bolton WK, Lee T, Li D, Neff TB, Urquilla PR, Sewell KL (2010) Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol: CJASN 5:1420–1428
Al-Lamki RS, Mayadas TN (2015) TNF receptors: signaling pathways and contribution to renal dysfunction. Kidney Int 87:281–296
Al-Lamki RS, Wang J, Vandenabeele P, Bradley JA, Thiru S, Luo D, Min W, Pober JS, Bradley JR (2005) TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J: Off Publ Fed Am Soc Exp Biol 19:1637–1645
Anders HJ, Vielhauer V, Schlondorff D (2003) Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int 63:401–415
Anders HJ, Belemezova E, Eis V, Segerer S, Vielhauer V, Perez de Lema G, Kretzler M, Cohen CD, Frink M, Horuk R, Hudkins KL, Alpers CE, Mampaso F, Schlondorff D (2004) Late onset of treatment with a chemokine receptor CCR4 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. J Am Soc Nephrol: JASN 15:1504–1513
Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, Stasiv Y, Zawadzki R, Berman L, Bushinsky DA (2015) Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial. JAMA 314:151–161
Barton M (2008) Reversal of proteinuric renal disease and the emerging role of endothelin. Nat Clin Pract Nephrol 4:490–501
Barutta F, Corbelli A, Mastrocola R, Gambino R, Di Marzo V, Pinach S, Rastaldi MP, Perin PC, Gruden G (2010) Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental diabetic nephropathy. Diabetes 59:1046–1054
Barutta F, Piscitelli F, Pinach S, Bruno G, Gambino R, Rastaldi MP, Salvidio G, Di Marzo V, Cavallo Perin P, Gruden G (2011) Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes 60:2386–2396
Barutta F, Grimaldi S, Franco I, Bellini S, Gambino R, Pinach S, Corbelli A, Bruno G, Rastaldi MP, Aveta T, Hirsch E, Di Marzo V, Gruden G (2014) Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice. Kidney Int 86:979–990
Barutta F, Grimaldi S, Gambino R, Vemuri K, Makriyannis A, Annaratone L, di Marzo V, Bruno G, Gruden G (2017) Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy. Nephrol Dialysis Transplant: Off Publ Eur Dial Transpl Assoc Eur Renal Assoc 32:1655–1665
Benigni A, Zoja C, Corna D, Orisio S, Longaretti L, Bertani T, Remuzzi G (1993) A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 44:440–444
Benigni A, Corna D, Maffi R, Benedetti G, Zoja C, Remuzzi G (1998) Renoprotective effect of contemporary blocking of angiotensin II and endothelin-1 in rats with membranous nephropathy. Kidney Int 54:353–359
Bertocchio JP, Warnock DG, Jaisser F (2011) Mineralocorticoid receptor activation and blockade: an emerging paradigm in chronic kidney disease. Kidney Int 79:1051–1060
Boffa JJ, Tharaux PL, Dussaule JC and Chatziantoniou C (2001) Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension (Dallas, Tex: 1979) 37:490–496
Bolignano D, Palmer SC, Navaneethan SD and Strippoli GF (2014) Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane database Syst Rev Cd007004
Borza CM, Su Y, Tran TL, Yu L, Steyns N, Temple KJ, Skwark MJ, Meiler J, Lindsley CW, Hicks BR, Leitinger B, Zent R, Pozzi A (2017) Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis. Matrix Biol: J Int Soc Matrix Biol 57–58:258–271
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New Engl J Med 345:861–869
Breyer MD, Susztak K (2016) The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discovery 15:568–588
Campbell D, Weir MR (2015) Defining, treating, and understanding chronic kidney disease—a complex disorder. J Clin Hypertens (Greenwich, Conn) 17:514–527
Castelino FV, Seiders J, Bain G, Brooks SF, King CD, Swaney JS, Lorrain DS, Chun J, Luster AD, Tager AM (2011) Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum 63:1405–1415
Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. New Engl J Med 354:610–621
Chen J, Chen JK, Nagai K, Plieth D, Tan M, Lee TC, Threadgill DW, Neilson EG, Harris RC (2012) EGFR signaling promotes TGFbeta-dependent renal fibrosis. J Am Soc Nephrol: JASN 23:215–224
Chen PM, Lai TS, Chen PY, Lai CF, Wu V, Chiang WC, Chen YM, Wu KD and Tsai TJ (2014) Renoprotective effect of combining pentoxifylline with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in advanced chronic kidney disease. J Formos Med Assoc = Taiwan yi zhi 113:219–226
Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M (2014) Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129:587–597
Chin MP, Bakris GL, Block GA, Chertow GM, Goldsberry A, Inker LA, Heerspink HJL, O’Grady M, Pergola PE, Wanner C, Warnock DG, Meyer CJ (2018) Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: post-hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. Am J Nephrol 47:40–47
Cho ME, Kopp JB (2010) Pirfenidone: an anti-fibrotic therapy for progressive kidney disease. Expert Opin Invest Drugs 19:275–283
Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB (2007) Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol: CJASN 2:906–913
de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM (2013) Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. New Engl J Med 369:2492–2503
Denby L, Ramdas V, Lu R, Conway BR, Grant JS, Dickinson B, Aurora AB, McClure JD, Kipgen D, Delles C, van Rooij E, Baker AH (2014) MicroRNA-214 antagonism protects against renal fibrosis. J Am Soc Nephrol: JASN 25:65–80
Desmedt V, Desmedt S, Delanghe JR, Speeckaert R, Speeckaert MM (2016) Galectin-3 in renal pathology: more than just an innocent bystander. Am J Nephrol 43:305–317
Dhaun N, Goddard J, Webb DJ (2006) The endothelin system and its antagonism in chronic kidney disease. J Am Soc Nephrol: JASN 17:943–955
Drechsler C, Delgado G, Wanner C, Blouin K, Pilz S, Tomaschitz A, Kleber ME, Dressel A, Willmes C, Krane V, Kramer BK, Marz W, Ritz E, van Gilst WH, van der Harst P, de Boer RA (2015) Galectin-3, renal function, and clinical outcomes: results from the LURIC and 4D studies. J Am Soc Nephrol: JASN 26:2213–2221
Egido J, Rojas-Rivera J, Mas S, Ruiz-Ortega M, Sanz AB, Gonzalez Parra E, Gomez-Guerrero C (2017) Atrasentan for the treatment of diabetic nephropathy. Expert Opin Invest Drugs 26:741–750
Fedorova LV, Sodhi K, Gatto-Weis C, Puri N, Hinds TD Jr, Shapiro JI, Malhotra D (2013) Peroxisome proliferator-activated receptor delta agonist, HPP593, prevents renal necrosis under chronic ischemia. PLoS ONE 8:e64436
Fernandes Bertocchi AP, Campanhole G, Wang PH, Goncalves GM, Damiao MJ, Cenedeze MA, Beraldo FC, de Paula Antunes Teixeira V, Dos Reis MA, Mazzali M, Pacheco-Silva A, Camara NO (2008) A role for galectin-3 in renal tissue damage triggered by ischemia and reperfusion injury. Transplant Int: Off J Eur Soc Organ Transplant 21:999–1007
Flamant M, Placier S, Rodenas A, Curat CA, Vogel WF, Chatziantoniou C, Dussaule JC (2006) Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease. J Am Soc Nephrol: JASN 17:3374–3381
Floege J, Eitner F, Alpers CE (2008) A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol: JASN 19:12–23
Francois H, Chatziantoniou C (2018) Renal fibrosis: recent translational aspects. Matrix Biol: J Int Soc Matrix Biol 68–69:318–332
Francois H, Lecru L (2018) The Role of cannabinoid receptors in renal diseases. Curr Med Chem 25:793–801
Frenay AR, Yu L, van der Velde AR, Vreeswijk-Baudoin I, Lopez-Andres N, van Goor H, Sillje HH, Ruifrok WP, de Boer RA (2015) Pharmacological inhibition of galectin-3 protects against hypertensive nephropathy. Am J Physiol Renal Physiol 308:F500–509
Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O’Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P (2013) Combined angiotensin inhibition for the treatment of diabetic nephropathy. New Engl J Med 369:1892–1903
Fukuda K, Yanagida T, Okuda S, Tamaki K, Ando T, Fujishima M (1996) Role of endothelin as a mitogen in experimental glomerulonephritis in rats. Kidney Int 49:1320–1329
Garber K (2009) Companies waver in efforts to target transforming growth factor beta in cancer. J Natl Cancer Inst 101:1664–1667
Gembardt F, Bartaun C, Jarzebska N, Mayoux E, Todorov VT, Hohenstein B, Hugo C (2014) The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol 307:F317–325
Gilbert RE, Zhang Y, Williams SJ, Zammit SC, Stapleton DI, Cox AJ, Krum H, Langham R, Kelly DJ (2012) A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat. PLoS ONE 7:e47160
Glowacki F, Savary G, Gnemmi V, Buob D, Van der Hauwaert C, Lo-Guidice JM, Bouye S, Hazzan M, Pottier N, Perrais M, Aubert S, Cauffiez C (2013) Increased circulating miR-21 levels are associated with kidney fibrosis. PLoS ONE 8:e58014
Goicoechea M, Garcia de Vinuesa S, Quiroga B, Verdalles U, Barraca D, Yuste C, Panizo N, Verde E, Munoz MA, Luno J (2012) Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. J Nephrol 25:969–975
Gomez IG, MacKenna DA, Johnson BG, Kaimal V, Roach AM, Ren S, Nakagawa N, Xin C, Newitt R, Pandya S, Xia TH, Liu X, Borza DB, Grafals M, Shankland SJ, Himmelfarb J, Portilla D, Liu S, Chau BN, Duffield JS (2015) Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest 125:141–156
Gomez IG, Nakagawa N, Duffield JS (2016) MicroRNAs as novel therapeutic targets to treat kidney injury and fibrosis. Am J Physiol Renal Physiol 310:F931–944
Gomez-Garre D, Ruiz-Ortega M, Ortego M, Largo R, Lopez-Armada MJ, Plaza JJ, Gonzalez E and Egido J (1996) Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension (Dallas, Tex: 1979) 27:885–892
Griendling KK (2006) NADPH oxidases: new regulators of old functions. Antioxid Redox Signal 8:1443–1445
Gross O, Girgert R, Beirowski B, Kretzler M, Kang HG, Kruegel J, Miosge N, Busse AC, Segerer S, Vogel WF, Muller GA, Weber M (2010) Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease. Matrix Biol: J Int Soc Matrix Biol 29:346–356
Guerrot D, Kerroch M, Placier S, Vandermeersch S, Trivin C, Mael-Ainin M, Chatziantoniou C, Dussaule JC (2011) Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy. Am J Pathol 179:83–91
Guerrot D, Dussaule JC, Mael-Ainin M, Xu-Dubois YC, Rondeau E, Chatziantoniou C, Placier S (2012) Identification of periostin as a critical marker of progression/reversal of hypertensive nephropathy. PLoS ONE 7:e31974
Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C, Iredale JP, Liu FT, Hughes J, Sethi T (2008) Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am J Pathol 172:288–298
Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K (2002) Endothelial function and oxidative stress in renovascular hypertension. New Engl J Med 346:1954–1962
Horiuchi K, Amizuka N, Takeshita S, Takamatsu H, Katsuura M, Ozawa H, Toyama Y, Bonewald LF, Kudo A (1999) Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta. J Bone Mineral Res: Off J Am Soc Bone Mineral Res 14:1239–1249
Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM (2001) Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J Am Soc Nephrol: JASN 12:1315–1325
Hou J, Xiong W, Cao L, Wen X, Li A (2015) Spironolactone add-on for preventing or slowing the progression of diabetic nephropathy: a meta-analysis. Clin Ther 37:2086–2103.e2010
Huaux F, Liu T, McGarry B, Ullenbruch M, Xing Z and Phan SH (2003) Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J immunol (Baltimore, Md: 1950) 171:5470–5481
Humphreys BD (2017) Mechanisms of renal fibrosis. Annu Rev Physiol 80:309–326
Hwang JH, Lee JP, Kim CT, Yang SH, Kim JH, An JN, Moon KC, Lee H, Oh YK, Joo KW, Kim DK, Kim YS, Lim CS (2016) Urinary periostin excretion predicts renal outcome in IgA nephropathy. Am J Nephrol 44:481–492
Jourdan T, Szanda G, Rosenberg AZ, Tam J, Earley BJ, Godlewski G, Cinar R, Liu Z, Liu J, Ju C, Pacher P, Kunos G (2014) Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy. Proc Natl Acad Sci USA 111:E5420–5428
Kerroch M, Guerrot D, Vandermeersch S, Placier S, Mesnard L, Jouanneau C, Rondeau E, Ronco P, Boffa JJ, Chatziantoniou C, Dussaule JC (2012) Genetic inhibition of discoidin domain receptor 1 protects mice against crescentic glomerulonephritis. FASEB J: Off Publ Fed Am Soc Exp Biol 26:4079–4091
Kerroch M, Alfieri C, Dorison A, Boffa JJ, Chatziantoniou C, Dussaule JC (2016) Protective effects of genetic inhibition of Discoidin Domain Receptor 1 in experimental renal disease. Scientific reports 6:21262
Klinkhammer BM, Goldschmeding R, Floege J, Boor P (2017) Treatment of renal fibrosis-turning challenges into opportunities. Adv Chronic Kidney Dis 24:117–129
Kok HM, Falke LL, Goldschmeding R, Nguyen TQ (2014) Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease. Nat Rev Nephrol 10:700–711
Kuc R, Davenport AP (2004) Comparison of endothelin-A and endothelin-B receptor distribution visualized by radioligand binding versus immunocytochemical localization using subtype selective antisera. J Cardiovasc Pharmacol 44(Suppl 1):S224–226
Kurts C, Panzer U, Anders HJ, Rees AJ (2013) The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol 13:738–753
Lassila M, Jandeleit-Dahm K, Seah KK, Smith CM, Calkin AC, Allen TJ, Cooper ME (2005) Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol: JASN 16:363–373
Lecru L, Desterke C, Grassin-Delyle S, Chatziantoniou C, Vandermeersch S, Devocelle A, Vernochet A, Ivanovski N, Ledent C, Ferlicot S, Dalia M, Said M, Beaudreuil S, Charpentier B, Vazquez A, Giron-Michel J, Azzarone B, Durrbach A, Francois H (2015) Cannabinoid receptor 1 is a major mediator of renal fibrosis. Kidney Int 88:72–84
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. New Engl J Med 345:851–860
Li G, Jin R, Norris RA, Zhang L, Yu S, Wu F, Markwald RR, Nanda A, Conway SJ, Smyth SS, Granger DN (2010) Periostin mediates vascular smooth muscle cell migration through the integrins alphavbeta3 and alphavbeta5 and focal adhesion kinase (FAK) pathway. Atherosclerosis 208:358–365
Li D, Lu Z, Jia J, Zheng Z, Lin S (2013) MiR-124 is related to podocytic adhesive capacity damage in STZ-induced uninephrectomized diabetic rats. Kidney Blood Press Res 37:422–431
Li Z, Liu X, Wang B, Nie Y, Wen J, Wang Q, Gu C (2017) Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton, Vic) 22:589–597
Liu F, Zhuang S (2016) Role of receptor tyrosine kinase signaling in renal fibrosis. Int J Mol Sci 17:972
Liu N, He S, Ma L, Ponnusamy M, Tang J, Tolbert E, Bayliss G, Zhao TC, Yan H, Zhuang S (2013) Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling. PLoS ONE 8:e54001
Liu F, Mei X, Zhang Y, Qi H, Wang J, Wang Y, Jiang W, Zhang X, Yan H, Zhuang S (2014) Association of peroxisome proliferator-activated receptorgamma gene Pro12Ala and C161T polymorphisms with cardiovascular risk factors in maintenance hemodialysis patients. Mol Biol Rep 41:7555–7565
Liu N, Wang L, Yang T, Xiong C, Xu L, Shi Y, Bao W, Chin YE, Cheng SB, Yan H, Qiu A, Zhuang S (2015) EGF receptor inhibition alleviates hyperuricemic nephropathy. J Am Soc Nephrol: JASN 26:2716–2729
Liu F, Wang L, Qi H, Wang J, Wang Y, Jiang W, Xu L, Liu N and Zhuang S (2017) Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. Clin Sci (London, England: 1979) 131:2125–2143
Llona-Minguez S, Ghassemian A, Helleday T (2015) Lysophosphatidic acid receptor (LPAR) modulators: the current pharmacological toolbox. Prog Lipid Res 58:51–75
Lo DJ, Farris AB, Song M, Leopardi F, Anderson DJ, Strobert EA, Ramakrishnan S, Turgeon NA, Mehta AK, Turnbull B, Maroni B, Violette SM, Kirk AD (2013) Inhibition of alphavbeta6 promotes acute renal allograft rejection in nonhuman primates. Am J Transplant: Off J Am Soc Transplant Am Soc Transplant Surg 13:3085–3093
Ly JP, Onay T, Sison K, Sivaskandarajah G, Sabbisetti V, Li L, Bonventre JV, Flenniken A, Paragas N, Barasch JM, Adamson SL, Osborne L, Rossant J, Schnermann J, Quaggin SE (2011) The Sweet Pee model for Sglt2 mutation. J Am Soc Nephrol: JASN 22:113–123
Mael-Ainin M, Abed A, Conway SJ, Dussaule JC, Chatziantoniou C (2014) Inhibition of periostin expression protects against the development of renal inflammation and fibrosis. J Am Soc Nephrol: JASN 25:1724–1736
Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G (2010) Avosentan for overt diabetic nephropathy. J Am Soc Nephrol: JASN 21:527–535
Manson SR, Niederhoff RA, Hruska KA, Austin PF (2011) Endogenous BMP-7 is a critical molecular determinant of the reversibility of obstruction-induced renal injuries. Am J Physiol Renal Physiol 301:F1293–1302
Marquez DF, Ruiz-Hurtado G, Ruilope LM, Segura J (2015) An update of the blockade of the renin angiotensin aldosterone system in clinical practice. Expert Opin Pharmacother 16:2283–2292
Martinez-Martinez E, Ibarrola J, Calvier L, Fernandez-Celis A, Leroy C, Cachofeiro V, Rossignol P, Lopez-Andres N (2016) Galectin-3 blockade reduces renal fibrosis in two normotensive experimental models of renal damage. PLoS ONE 11:e0166272
McCormack PL (2015) Nintedanib: first global approval. Drugs 75:129–139
McVicker BL, Bennett RG (2017) Novel anti-fibrotic therapies. Front Pharmacol 8:318
Meng XM, Tang PM, Li J, Lan HY (2015) TGF-beta/Smad signaling in renal fibrosis. Front Physiol 6:82
Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S (2002) Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol: JASN 13(Suppl 1):S14–21
Nam DH, Lee MH, Kim JE, Song HK, Kang YS, Lee JE, Kim HW, Cha JJ, Hyun YY, Kim SH, Han SY, Han KH, Han JY, Cha DR (2012) Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. Endocrinology 153:1387–1396
Okamura DM, Pasichnyk K, Lopez-Guisa JM, Collins S, Hsu DK, Liu FT, Eddy AA (2011) Galectin-3 preserves renal tubules and modulates extracellular matrix remodeling in progressive fibrosis. Am J Physiol Renal Physiol 300:F245–253
Opocensky M, Kramer HJ, Backer A, Vernerova Z, Eis V, Cervenka L, Certikova Chabova V, Tesar V and Vaneckova I (2006) Late-onset endothelin-A receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension (Dallas, Tex: 1979) 48:965–971
Pang M, Kothapally J, Mao H, Tolbert E, Ponnusamy M, Chin YE, Zhuang S (2009) Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol 297:F996–f1005
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P (2001) The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. New Engl J Med 345:870–878
Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA (2012) Cardiorenal end points in a trial of aliskiren for type 2 diabetes. New Engl J Med 367:2204–2213
Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG (2011) Bardoxolone methyl and kidney function in CKD with type 2 diabetes. New Engl J Med 365:327–336
Perkins RM, Aboudara MC, Uy AL, Olson SW, Cushner HM, Yuan CM (2009) Effect of pentoxifylline on GFR decline in CKD: a pilot, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis 53:606–616
Prakoura N, Chatziantoniou C (2017) Periostin and discoidin domain receptor 1: new biomarkers or targets for therapy of renal disease. Frontiers in medicine 4:52
RamachandraRao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, Okada S, Shaw MA, Sharma K (2009) Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol: JASN 20:1765–1775
Reich B, Schmidbauer K, Rodriguez Gomez M, Johannes Hermann F, Gobel N, Bruhl H, Ketelsen I, Talke Y, Mack M (2013) Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int 84:78–89
Ricardo SD, van Goor H, Eddy AA (2008) Macrophage diversity in renal injury and repair. J Clin Invest 118:3522–3530
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. New Engl J Med 370:2071–2082
Robalo-Cordeiro C, Campos P, Carvalho L, Borba A, Clemente S, Freitas S, Furtado S, Jesus JM, Leal C, Marques A, Melo N, Souto-Moura C, Neves S, Sousa V, Santos A, Morais A (2017) Idiopathic pulmonary fibrosis in the era of antifibrotic therapy: Searching for new opportunities grounded in evidence. Revista portuguesa de pneumologia 23:287–293
Saccon F, Gatto M, Ghirardello A, Iaccarino L, Punzi L, Doria A (2017) Role of galectin-3 in autoimmune and non-autoimmune nephropathies. Autoimmun Rev 16:34–47
Saito Y, Nakao K, Mukoyama M, Shirakami G, Itoh H, Yamada T, Arai H, Hosoda K, Suga S, Jougasaki M et al (1990) Application of monoclonal antibodies for endothelin to hypertensive research. Hypertension (Dallas, Tex: 1979) 15:734–738
Saleh MA, Pollock JS, Pollock DM (2011) Distinct actions of endothelin A-selective versus combined endothelin A/B receptor antagonists in early diabetic kidney disease. J Pharmacol Exp Ther 338:263–270
Satirapoj B, Wang Y, Chamberlin MP, Dai T, LaPage J, Phillips L, Nast CC, Adler SG (2012) Periostin: novel tissue and urinary biomarker of progressive renal injury induces a coordinated mesenchymal phenotype in tubular cells. Nephrol Dialysis Transplant: Off Publ Eur Dial Transpl Asso Eur Renal Assoc 27:2702–2711
Savikko J, Taskinen E, Von Willebrand E (2003) Chronic allograft nephropathy is prevented by inhibition of platelet-derived growth factor receptor: tyrosine kinase inhibitors as a potential therapy. Transplantation 75:1147–1153
Schauerte C, Hubner A, Rong S, Wang S, Shushakova N, Mengel M, Dettling A, Bang C, Scherf K, Koelling M, Melk A, Haller H, Thum T, Lorenzen JM (2017) Antagonism of profibrotic microRNA-21 improves outcome of murine chronic renal allograft dysfunction. Kidney Int 92:646–656
Sen K, Lindenmeyer MT, Gaspert A, Eichinger F, Neusser MA, Kretzler M, Segerer S, Cohen CD (2011) Periostin is induced in glomerular injury and expressed de novo in interstitial renal fibrosis. Am J Pathol 179:1756–1767
Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, Francos B, Sharma S, Falkner B, McGowan TA, Donohue M, Ramachandrarao S, Xu R, Fervenza FC, Kopp JB (2011) Pirfenidone for diabetic nephropathy. J Am Soc Nephrol: JASN 22:1144–1151
Strutz F, Zeisberg M, Renziehausen A, Raschke B, Becker V, van Kooten C, Muller G (2001) TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int 59:579–592
Sugimoto H, LeBleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, Okada H, Carlson W Jr, Bey P, Rusckowski M, Tampe B, Tampe D, Kanasaki K, Zeisberg M, Kalluri R (2012) Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat Med 18:396–404
Sullivan T, Miao Z, Dairaghi DJ, Krasinski A, Wang Y, Zhao BN, Baumgart T, Ertl LS, Pennell A, Seitz L, Powers J, Zhao R, Ungashe S, Wei Z, Boring L, Tsou CL, Charo I, Berahovich RD, Schall TJ, Jaen JC (2013) CCR118 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR118 knockin mice. Am J Physiol Renal Physiol 305:F1288–1297
Swencki-Underwood B, Mills JK, Vennarini J, Boakye K, Luo J, Pomerantz S, Cunningham MR, Farrell FX, Naso MF, Amegadzie B (2008) Expression and characterization of a human BMP-7 variant with improved biochemical properties. Protein Expr Purif 57:312–319
Tager AM, LaCamera P, Shea BS, Campanella GS, Selman M, Zhao Z, Polosukhin V, Wain J, Karimi-Shah BA, Kim ND, Hart WK, Pardo A, Blackwell TS, Xu Y, Chun J, Luster AD (2008) The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 14:45–54
Tahrani AA, Barnett AH, Bailey CJ (2016) Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol 12:566–592
Tam J (2016) The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases. J Basic Clin Physiol Pharmacol 27:267–276
Tampe B, Zeisberg M (2014a) Evidence for the involvement of epigenetics in the progression of renal fibrogenesis. Nephrol Dialysis Transplant: Off Publ Eur Dial Transpl Asso Eur Renal Assoc 29(Suppl 1):i1–i8
Tampe D, Zeisberg M (2014b) Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol 10:226–237
Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, Takeuchi M, Raghu G, Kudoh S, Nukiwa T (2010) Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 35:821–829
Trachtman H, Fervenza FC, Gipson DS, Heering P, Jayne DR, Peters H, Rota S, Remuzzi G, Rump LC, Sellin LK, Heaton JP, Streisand JB, Hard ML, Ledbetter SR, Vincenti F (2011) A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 79:1236–1243
Tsuchiyama Y, Wada J, Zhang H, Morita Y, Hiragushi K, Hida K, Shikata K, Yamamura M, Kanwar YS, Makino H (2000) Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int 58:1941–1952
Udi S, Hinden L, Earley B, Drori A, Reuveni N, Hadar R, Cinar R, Nemirovski A, Tam J (2017) Proximal tubular cannabinoid-1 receptor regulates obesity-induced CKD. J Am Soc Nephrol: JASN 28:3518–3532
Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T (2014) SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 306:F194–204
Van Bergen T, Marshall D, Van de Veire S, Vandewalle E, Moons L, Herman J, Smith V, Stalmans I (2013) The role of LOX and LOXL2 in scar formation after glaucoma surgery. Invest Ophthalmol Vis Sci 54:5788–5796
Vethe H, Finne K, Skogstrand T, Vaudel M, Vikse BE, Hultstrom M, Placier S, Scherer A, Tenstad O, Marti HP (2015) Distinct protein signature of hypertension-induced damage in the renal proteome of the two-kidney, one-clip rat model. J Hypertens 33:126–135
Vincenti F, Fervenza FC, Campbell KN, Diaz M, Gesualdo L, Nelson P, Praga M, Radhakrishnan J, Sellin L, Singh A, Thornley-Brown D, Veronese FV, Accomando B, Engstrand S, Ledbetter S, Lin J, Neylan J, Tumlin J (2017) A phase 2, double-blind, placebo-controlled, randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis. Kidney Int Rep 2:800–810
Virdis A, Neves MF, Amiri F, Touyz RM, Schiffrin EL (2004) Role of NAD(P)H oxidase on vascular alterations in angiotensin II-infused mice. J Hypertens 22:535–542
Wallace DP, White C, Savinkova L, Nivens E, Reif GA, Pinto CS, Raman A, Parnell SC, Conway SJ, Fields TA (2014) Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease. Kidney Int 85:845–854
Wang W, Liu F, Chen N (2007) Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists attenuate the profibrotic response induced by TGF-beta1 in renal interstitial fibroblasts. Mediat Inflamm 2007:62641
Weir MR, Bakris GL, Gross C, Mayo MR, Garza D, Stasiv Y, Yuan J, Berman L, Williams GH (2016) Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors. Kidney Int 90:696–704
Wen WX, Lee SY, Siang R, Koh RY (2017) Repurposing pentoxifylline for the treatment of fibrosis: an overview. Adv Therapy 34:1245–1269
Wenzel RR, Littke T, Kuranoff S, Jurgens C, Bruck H, Ritz E, Philipp T, Mitchell A (2009) Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol: JASN 20:655–664
Wilcox CS (2002) Reactive oxygen species: roles in blood pressure and kidney function. Curr Hypertens Rep 4:160–166
Woodcock HV, Molyneaux PL, Maher TM (2013) Reducing lung function decline in patients with idiopathic pulmonary fibrosis: potential of nintedanib. Drug Des Dev Therapy 7:503–510
Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, Wajs E, Figueroa K, Jiang J, Law G, Usiskin K, Meininger G (2014) Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 16:1016–1027
Yan Y, Ma L, Zhou X, Ponnusamy M, Tang J, Zhuang MA, Tolbert E, Bayliss G, Bai J and Zhuang S (2015) Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int
Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C (2008) Telmisartan, ramipril, or both in patients at high risk for vascular events. New Engl J Med 358:1547–1559
Zarjou A, Yang S, Abraham E, Agarwal A, Liu G (2011) Identification of a microRNA signature in renal fibrosis: role of miR-21. Am J Physiol Renal Physiol 301:F793–801
Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968
Zhou X, Zang X, Ponnusamy M, Masucci MV, Tolbert E, Gong R, Zhao TC, Liu N, Bayliss G, Dworkin LD, Zhuang S (2016) Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression. J Am Soc Nephrol: JASN 27:2092–2108
Zoja C, Corna D, Rottoli D, Zanchi C, Abbate M, Remuzzi G (2006) Imatinib ameliorates renal disease and survival in murine lupus autoimmune disease. Kidney Int 70:97–103
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Liu, F., Zhuang, S. (2019). New Therapies for the Treatment of Renal Fibrosis. In: Liu, BC., Lan, HY., Lv, LL. (eds) Renal Fibrosis: Mechanisms and Therapies. Advances in Experimental Medicine and Biology, vol 1165. Springer, Singapore. https://doi.org/10.1007/978-981-13-8871-2_31
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