Current Opinion for Hypertension in Renal Fibrosis

  • Hai-Jian SunEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1165)


Arterial hypertension remains to be a serious problem with considerable morbidity and mortality worldwide in the present age. Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, renal failure, and heart failure. Hypertensive nephropathy is the second leading cause of death in chronic kidney disease (CKD) around the world. Long-time hypertension loading results in renal interstitial fibrosis, which is associated with aberrant activation of renal fibroblasts and excessive generation of extracellular matrix (ECM) proteins. Increasing evidence supported that proteinuria, tubular hypertrophy, oxidative stress, activation of renin–aldosterone–angiotensin system (RAAS), collagen turnover, chronic inflammation, and vasoactive substances synergistically contributed to the pathogenesis of hypertensive renal fibrosis. However, the mechanisms involving the pathogenesis of hypertensive renal fibrosis are complex and not fully understood. Also, the effective clinical therapy to halt or even reverse renal fibrosis in hypertension is still limited. In this chapter, we aimed to provide an overview of the main pathophysiologic and mechanistic features of renal fibrosis under hypertensive state. The completion of the studies in these directions would improve our understanding of renal fibrosis in hypertension and also help us better screen treatment strategies for preventing renal destruction associated with hypertension.


Hypertension Kidney Fibrosis Chronic kidney disease 



We would like to thank Professor J.S.B. (National University of Singapore) for helpful discussing and revising the overall the manuscript.


  1. Bae EH, Kim IJ, Ma SK, Kim SW (2010) Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats. Hypertens Res 33:255–262CrossRefGoogle Scholar
  2. Bascands JL, Schanstra JP (2004) Bradykinin and renal fibrosis: have we ACE’d it? J Am Soc Nephrol 15:2504–2506CrossRefGoogle Scholar
  3. Cano A, Nieto MA (2008) Non-coding RNAs take centre stage in epithelial- to- mesenchymal transition. Trends Cell Biol 18:357–359CrossRefGoogle Scholar
  4. Chatziantoniou C, Boffa JJ, Tharaux PL, Flamant M, Ronco P, Dussaule JC (2004) Progression and regression in renal vascular and glomerular fibrosis. Int J Exp Pathol 85:1–11CrossRefGoogle Scholar
  5. Decleves AE, Sharma K (2014) Novel targets of antifibrotic and anti-inflammatory treatment in CKD. Nat Rev Nephrol 10:257–267CrossRefGoogle Scholar
  6. Dussaule JC, Guerrot D, Huby AC, Chadjichristos C, Shweke N, Boffa JJ et al (2011) The role of cell plasticity in progression and reversal of renal fibrosis. Int J Exp Pathol 92:151–157CrossRefGoogle Scholar
  7. el Nahas AM, Muchaneta-Kubara EC, Essawy M, Soylemezoglu O (1997) Renal fibrosis: insights into pathogenesis and treatment. Int J Biochem Cell Biol 29:55–62CrossRefGoogle Scholar
  8. Fogo AB (2001a) Progression and potential regression of glomerulosclerosis. Kidney Int 59:804–819CrossRefGoogle Scholar
  9. Fogo AB (2001b) Renal fibrosis and the renin-angiotensin system. Adv Nephrol Necker Hosp 31:69–87PubMedGoogle Scholar
  10. Franco M, Martinez F, Quiroz Y, Galicia O, Bautista R, Johnson RJ et al (2007) Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt- sensitive hypertension. Am J Physiol Regul Integr Comp Physiol 293:R251–R256CrossRefGoogle Scholar
  11. Ghaderian SB, Beladi-Mousavi SS (2014) The role of diabetes mellitus and hypertension in chronic kidney disease. J Renal Inj Prev 3:109–110PubMedPubMedCentralGoogle Scholar
  12. Grabias BM, Konstantopoulos K (2014) The physical basis of renal fibrosis: effects of altered hydrodynamic forces on kidney homeostasis. Am J Physiol Renal Physiol 306:F473–F485CrossRefGoogle Scholar
  13. Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu Rev Med 57:365–380CrossRefGoogle Scholar
  14. Hart PD, Bakris GL (2010) Hypertensive nephropathy: prevention and treatment recommendations. Expert Opin Pharmacother 11:2675–2686CrossRefGoogle Scholar
  15. Harwani SC, Chapleau MW, Legge KL, Ballas ZK, Abboud FM (2012) Neurohormonal modulation of the innate immune system is proinflammatory in the prehypertensive spontaneously hypertensive rat, a genetic model of essential hypertension. Circ Res 111:1190–1197CrossRefGoogle Scholar
  16. He T, Xiong J, Nie L, Yu Y, Guan X, Xu X et al (2016) Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway. J Mol Med (Berl) 94:1359–1371CrossRefGoogle Scholar
  17. Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S (2007) Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 112:417–428CrossRefGoogle Scholar
  18. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110:341–350CrossRefGoogle Scholar
  19. Jennings BL, Anderson LJ, Estes AM, Yaghini FA, Fang XR, Porter J et al (2012) Cytochrome P450 1B1 contributes to renal dysfunction and damage caused by angiotensin II in mice. Hypertension 59:348–354CrossRefGoogle Scholar
  20. Jia Z, Guo X, Zhang H, Wang MH, Dong Z, Yang T (2008) Microsomal prostaglandin synthase-1-derived prostaglandin E2 protects against angiotensin II-induced hypertension via inhibition of oxidative stress. Hypertension 52:952–959CrossRefGoogle Scholar
  21. Khan NS, Song CY, Thirunavukkarasu S, Fang XR, Bonventre JV, Malik KU (2016) Cytosolic phospholipase A2α is essential for renal dysfunction and end-organ damage associated with angiotensin II-induced hypertension. Am J Hypertens 29:258–265CrossRefGoogle Scholar
  22. Klahr S, Morrissey JJ (2000) The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int Suppl 75:S7–14CrossRefGoogle Scholar
  23. Klahr S, Morrissey J (2002) Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol 283:F861–F875CrossRefGoogle Scholar
  24. Kusunoki H, Taniyama Y, Rakugi H, Morishita R (2013) Cardiac and renal protective effects of irbesartan via peroxisome proliferator- activated receptorgamma- hepatocyte growth factor pathway independent of angiotensin II Type 1a receptor blockade in mouse model of salt-sensitive hypertension. J Am Heart Assoc 2:e000103CrossRefGoogle Scholar
  25. Lee SY, Kim SI, Choi ME (2015) Therapeutic targets for treating fibrotic kidney diseases. Transl Res 165:512–530CrossRefGoogle Scholar
  26. Liao TD, Yang XP, Liu YH, Shesely EG, Cavasin MA, Kuziel WA et al (2008) Role of inflammation in the development of renal damage and dysfunction in angiotensin II-induced hypertension. Hypertension 52:256–263CrossRefGoogle Scholar
  27. Liu Y, Taylor NE, Lu L, Usa K, Cowley AW Jr, Ferreri NR et al (2010) Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes. Hypertension 55:974–982CrossRefGoogle Scholar
  28. Lombardi DM, Viswanathan M, Vio CP, Saavedra JM, Schwartz SM, Johnson RJ (2001) Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent. Nephron 87:66–74CrossRefGoogle Scholar
  29. Lv W, Booz GW, Fan F, Wang Y, Roman RJ (2018) Oxidative stress and renal fibrosis: recent insights for the development of novel therapeutic strategies. Front Physiol 9:105CrossRefGoogle Scholar
  30. Macconi D, Tomasoni S, Romagnani P, Trionfini P, Sangalli F, Mazzinghi B et al (2012) MicroRNA-324-3p promotes renal fibrosis and is a target of ACE inhibition. J Am Soc Nephrol 23:1496–1505CrossRefGoogle Scholar
  31. Manning RD Jr, Tian N, Meng S (2005) Oxidative stress and antioxidant treatment in hypertension and the associated renal damage. Am J Nephrol 25:311–317CrossRefGoogle Scholar
  32. Marko L, Kvakan H, Park JK, Qadri F, Spallek B, Binger KJ et al (2012) Interferon- gamma signaling inhibition ameliorates angiotensin II- induced cardiac damage. Hypertension 60:1430–1436CrossRefGoogle Scholar
  33. McCarty MF (2006) Adjuvant strategies for prevention of glomerulosclerosis. Med Hypotheses 67:1277–1296CrossRefGoogle Scholar
  34. McMaster WG, Kirabo A, Madhur MS, Harrison DG (2015) Inflammation, immunity, and hypertensive end- organ damage. Circ Res 116:1022–1033CrossRefGoogle Scholar
  35. Mehta PK, Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292:C82–C97CrossRefGoogle Scholar
  36. Modlinger PS, Wilcox CS, Aslam S (2004) Nitric oxide, oxidative stress, and progression of chronic renal failure. Semin Nephrol 24:354–365CrossRefGoogle Scholar
  37. Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Hampich F et al (2002) Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol 161:1679–1693CrossRefGoogle Scholar
  38. Petrillo F, Iervolino A, Zacchia M, Simeoni A, Masella C, Capolongo G et al (2017) MicroRNAs in renal diseases: a potential novel therapeutic target. Kidney Dis (Basel) 3:111–119CrossRefGoogle Scholar
  39. Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116:288–296CrossRefGoogle Scholar
  40. Rodrigues-Diez R, Carvajal-Gonzalez G, Sanchez-Lopez E, Rodriguez-Vita J, Rodrigues Diez R, Selgas R et al (2008) Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways. Pharm Res 25:2447–2461CrossRefGoogle Scholar
  41. Ruiz-Ortega M, Esteban V, Ruperez M, Sanchez-Lopez E, Rodriguez-Vita J, Carvajal G et al (2006a) Renal and vascular hypertension-induced inflammation: role of angiotensin II. Curr Opin Nephrol Hypertens 15:159–166CrossRefGoogle Scholar
  42. Ruiz-Ortega M, Ruperez M, Esteban V, Rodriguez-Vita J, Sanchez-Lopez E, Carvajal G et al (2006b) Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol Dial Transplant 21:16–20CrossRefGoogle Scholar
  43. Ruster C, Wolf G (2011) Angiotensin II as a morphogenic cytokine stimulating renal fibrogenesis. J Am Soc Nephrol 22:1189–1199CrossRefGoogle Scholar
  44. Saad S, Stanners SR, Yong R, Tang O, Pollock CA (2010) Notch mediated epithelial to mesenchymal transformation is associated with increased expression of the Snail transcription factor. Int J Biochem Cell Biol 42:1115–1122CrossRefGoogle Scholar
  45. Sun L, Zhang D, Liu F, Xiang X, Ling G, Xiao L et al (2011) Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192. J Pathol 225:364–377CrossRefGoogle Scholar
  46. Tampe B, Zeisberg M (2014) Contribution of genetics and epigenetics to progression of kidney fibrosis. Nephrol Dial Transplant 29(Suppl 4): iv72–iv79CrossRefGoogle Scholar
  47. Tian N, Rose RA, Jordan S, Dwyer TM, Hughson MD, Manning RD Jr (2006) N-acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension. J Hypertens 24:2263–2270CrossRefGoogle Scholar
  48. Touyz RM, Tabet F, Schiffrin EL (2003) Redox-dependent signalling by angiotensin II and vascular remodelling in hypertension. Clin Exp Pharmacol Physiol 30:860–866CrossRefGoogle Scholar
  49. Udani S, Lazich I, Bakris GL (2011) Epidemiology of hypertensive kidney disease. Nat Rev Nephrol 7:11–21CrossRefGoogle Scholar
  50. Wang G, Kwan BC, Lai FM, Choi PC, Chow KM, Li PK et al (2010) Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis. Am J Hypertens 23:78–84CrossRefGoogle Scholar
  51. Wang Y, Mu JJ, Liu FQ, Ren KY, Xiao HY, Yang Z et al (2014) Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure. Braz J Med Biol Res 47:223–230CrossRefGoogle Scholar
  52. Wei Q, Mi QS, Dong Z (2013) The regulation and function of microRNAs in kidney diseases. IUBMB Life 65:602–614CrossRefGoogle Scholar
  53. Wolf G (2006) Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway. Kidney Int 70:1914–1919CrossRefGoogle Scholar
  54. Zambrano S, Blanca AJ, Ruiz-Armenta MV, Miguel-Carrasco JL, Arevalo M, Mate A et al (2014) l-carnitine attenuates the development of kidney fibrosis in hypertensive rats by upregulating PPAR-gamma. Am J Hypertens 27:460–470CrossRefGoogle Scholar
  55. Zhang W, Wang W, Yu H, Zhang Y, Dai Y, Ning C et al (2012) Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage. Hypertension 59:136–144CrossRefGoogle Scholar
  56. Zhang Y, Peng W, Ao X, Dai H, Yuan L, Huang X et al (2015) TAK-242, a toll-like receptor 4 antagonist, protects against aldosterone-induced cardiac and renal injury. PLoS ONE 10:e0142456CrossRefGoogle Scholar
  57. Zhao W, Chen SS, Chen Y, Ahokas RA, Sun Y (2008) Kidney fibrosis in hypertensive rats: role of oxidative stress. Am J Nephrol 28:548–554CrossRefGoogle Scholar
  58. Zhou B, Mu J, Gong Y, Lu C, Zhao Y, He T et al (2017) Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-beta-mediated Nox4 expression. Redox Biol 11:390–402CrossRefGoogle Scholar
  59. Zhou Y, Yu J, Liu J, Cao R, Su W, Li S et al (2018) Induction of cytochrome P450 4A14 contributes to angiotensin II-induced renal fibrosis in mice. Biochim Biophys Acta 1864:860–870CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Personalised recommendations