Skip to main content

Advertisement

SpringerLink
Log in

Unilateral ureteral obstruction: beyond obstruction

  • Nephrology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Unilateral ureteral obstruction is a popular experimental model of renal injury. However, the study of the kidney response to urinary tract obstruction is only one of several advantages of this model. Unilateral ureteral obstruction causes subacute renal injury characterized by tubular cell injury, interstitial inflammation and fibrosis. For this reason, it serves as a model both of irreversible acute kidney injury and of events taking place during human chronic kidney disease. Being a unilateral disease, it is not useful to study changes in global kidney function, but has the advantage of a low mortality and the availability of an internal control (the non-obstructed kidney). Experimental unilateral ureteral obstruction has illustrated the molecular mechanisms of apoptosis, inflammation and fibrosis, all three key processes in kidney injury of any cause, thus providing information beyond obstruction. Recently this model has supported key concepts on the role in kidney fibrosis of epithelial–mesenchymal transition, tubular epithelial cell G2/M arrest, the anti-aging hormone Klotho and renal innervation. We now review the experimental model and its contribution to identifying novel therapeutic targets in kidney injury and fibrosis, independently of the noxa.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

α-SMA:

Alpha-smooth muscle actin

ACE:

Angiotensin-converting enzyme

AKI:

Acute kidney injury

Alk3:

Activin-like kinase-3

AngII:

Angiotensin II

ARB:

Angiotensin receptor blocker

B1R:

Kinin B1 receptor

BMP-7:

Bone morphogenetic protein-7

CGRP:

Calcitonin gene-related peptide

CKD:

Chronic kidney disease

ECM:

Extracellular matrix

EGFR:

Epithelial growth factor

EMT:

Epithelial to mesenchymal transition

HE4:

Human epididymis protein 4

H/E:

Hematoxilyn/eosin staining

HIPK2:

Homeo-domain-interacting protein kinase 2

ICAM-1:

Intercelullar adhesion molecule-1

MAPK:

Mitogen-acivated protein kinase

MCP-1:

Macrophages chemoattractant protein-1

NMDA:

N-methyl-d-aspartate

NMDAR:

N-methyl-d-aspartate receptor

OPN:

Osteopontin

PAI-1:

Plasminogen activator inhibitor-1

PPARα:

Peroxisome proliferator-activated receptor alpha

RIPK1:

Receptor-interacting serine/threonine protein kinase 1

RIPK2:

Receptor-interacting serine/threonine protein kinase 2

TGF-β1:

Transforming growth factor-beta 1

TNFR1:

Tumor necrosis factor receptor-1

TNFR2:

Tumor necrosis factor receptor-2

TNFα:

Tumor necrosis factor-alpha

TMS:

Trichrome Masson’s staining

TWEAK:

TNF-like weak inducer of apoptosis

UUO:

Unilateral ureteral obstruction

VCAM-1:

Vascular cell adhesion molecule-1

VDR:

Vitamin D receptor

References

  1. Better OS, Arieff AI, Massry SG, Kleeman CR, Maxwell MH (1973) Studies on renal function after relief of complete unilateral ureteral obstruction of three months’ duration in man. Am J Med 54:234–240

    PubMed  CAS  Google Scholar 

  2. Sacks SH, Aparicio SA, Bevan A, Oliver DO, Will EJ, Davison AM (1989) Late renal failure due to prostatic outflow obstruction: a preventable disease. BMJ 298:156–159

    PubMed Central  PubMed  CAS  Google Scholar 

  3. Ucero AC, Benito-Martin A, Fuentes-Calvo I et al (2013) TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras-dependent proliferation of cultured renal fibroblast. Biochim Biophys Acta 1832(10):1744–1755

    Google Scholar 

  4. Ulm AH, Miller F (1962) An operation to produce experimental reversible hydronephrosis in dogs. J Urol 88:337–341

    PubMed  CAS  Google Scholar 

  5. Shokeir AA (1995) Partial ureteral obstruction: a new variable and reversible canine experimental model. Urology 45:953–957

    PubMed  CAS  Google Scholar 

  6. Wen JG, Frokiaer J, Zhao JB, Ringgaard S, Jorgensen TM, Djurhuus JC (2002) Severe partial ureteric obstruction in newborn rats can produce renal dysplasia. BJU Int 89:740–745

    PubMed  CAS  Google Scholar 

  7. Josephson S, Jacobsson E, Larsson E (1997) Experimental partial ureteric obstruction in newborn rats. IX. Renal morphology and function after 1 year of obstruction. Urol Int 59:16–22

    PubMed  CAS  Google Scholar 

  8. Eskild-Jensen A, Frøkiaer J, Djurhuus JC, Jørgensen TM, Nyengaard JR (2002) Reduced number of glomeruli in kidneys with neonatally induced partial ureteropelvic obstruction in pigs. J Urol 167:1435–1439

    PubMed  Google Scholar 

  9. Chevalier RL, Kaiser DL (1984) Chronic partial ureteral obstruction in the neonatal guinea pig. I. Influence of uninephrectomy on growth and hemodynamics. Pediatr Res 18:1266–1271

    PubMed  CAS  Google Scholar 

  10. Chevalier RL (1984) Chronic partial ureteral obstruction in the neonatal guinea pig. II. Pressure gradients affecting glomerular filtration rate. Pediatr Res 18:1271–1277

    PubMed  CAS  Google Scholar 

  11. Eskild-Jensen A, Paulsen LF, Wogensen L et al (2007) AT1 receptor blockade prevents interstitial and glomerular apoptosis but not fibrosis in pigs with neonatal induced partial unilateral ureteral obstruction. Am J Physiol Renal Physiol 292:F1771–F1781

    PubMed  CAS  Google Scholar 

  12. Puri TS, Shakaib MI, Chang A et al (2010) Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background. Am J Physiol Renal Physiol 298:F1024–F1032

    PubMed Central  PubMed  CAS  Google Scholar 

  13. Chaabane W, Praddaude F, Buleon M et al (2013) Renal functional decline and glomerulotubular injury are arrested but not restored by release of unilateral ureteral obstruction (UUO). Am J Physiol Renal Physiol 304:F432–F439

    PubMed  CAS  Google Scholar 

  14. Harris K, Klahr S, Schreiner G (1993) Obstructive nephropathy: from mechanical disturbance to immune activation?. Exp Nephrol 1:198–204

    Google Scholar 

  15. Klahr S (1991) Pathophysiology of obstructive nephropathy: a 1991 update. Semin Nephrol 11:156–168

    PubMed  CAS  Google Scholar 

  16. Wen JG, Frøkiaer J, Jørgensen TM, Djurhuus JC (1999) Obstructive nephropathy: an update of the experimental research. Urol Res 27:29–39

    PubMed  CAS  Google Scholar 

  17. Diamond JR, Kees-Folts D, Ricardo SD, Pruznak A, Eufemio M (1995) Early and persistent up-regulated expression of renal cortical osteopontin in experimental hydronephrosis. Am J Pathol 146:1455–1466

    PubMed Central  PubMed  CAS  Google Scholar 

  18. Yoo KH, Thornhill BA, Forbes MS et al (2006) Osteopontin regulates renal apoptosis and interstitial fibrosis in neonatal chronic unilateral ureteral obstruction. Kidney Int 70:1735–1741

    PubMed  CAS  Google Scholar 

  19. Schreiner GF, Harris KP, Purkerson ML, Klahr S (1988) Immunological aspects of acute ureteral obstruction: immune cell infiltrate in the kidney. Kidney Int 34:487–493

    PubMed  CAS  Google Scholar 

  20. Vielhauer V, Anders HJ, Mack M et al (2001) Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes. J Am Soc Nephrol 12:1173–1187

    PubMed  CAS  Google Scholar 

  21. Duymelinck C, Dauwe SE, De Greef KE, Ysebaert DK, Verpooten GA, De Broe ME (2000) TIMP-1 gene expression and PAI-1 antigen after unilateral ureteral obstruction in the adult male rat. Kidney Int 58:1186–1201

    PubMed  CAS  Google Scholar 

  22. Misseri R, Meldrum DR, Dagher P, Hile K, Rink RC, Meldrum KK (2004) Unilateral ureteral obstruction induces renal tubular cell production of tumor necrosis factor-alpha independent of inflammatory cell infiltration. J Urol 172:1595–1599

    PubMed  CAS  Google Scholar 

  23. Meldrum KK, Metcalfe P, Leslie JA, Misseri R, Hile KL, Meldrum DR (2006) TNF-alpha neutralization decreases nuclear factor-kappaB activation and apoptosis during renal obstruction. J Surg Res 131:182–188

    PubMed  CAS  Google Scholar 

  24. Morrissey JJ, Klahr S (1997) Rapid communication. Enalapril decreases nuclear factor kappa B activation in the kidney with ureteral obstruction. Kidney Int 52:926–933

    PubMed  CAS  Google Scholar 

  25. Morrissey JJ, Klahr S (1999) Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. Am J Physiol 276:F39–F45

    PubMed  CAS  Google Scholar 

  26. Sanz AB, Sanchez-Nino MD, Ramos AM et al (2010) NF-kappaB in renal inflammation. J Am Soc Nephrol 21:1254–1262

    PubMed  CAS  Google Scholar 

  27. Ricardo SD, Levinson ME, DeJoseph MR, Diamond JR (1996) Expression of adhesion molecules in rat renal cortex during experimental hydronephrosis. Kidney Int 50:2002–2010

    PubMed  CAS  Google Scholar 

  28. Morrissey JJ, Klahr S (1998) Differential effects of ACE and AT1 receptor inhibition on chemoattractant and adhesion molecule synthesis. Am J Physiol 274:F580–F586

    PubMed  CAS  Google Scholar 

  29. Le Meur Y, Tesch GH, Hill PA et al (2002) Macrophage accumulation at a site of renal inflammation is dependent on the M-CSF/c-fms pathway. J Leukoc Biol 72:530–537

    PubMed  Google Scholar 

  30. Kaneto H, Ohtani H, Fukuzaki A et al (1999) Increased expression of TGF-beta1 but not of its receptors contributes to human obstructive nephropathy. Kidney Int 56:2137–2146

    PubMed  CAS  Google Scholar 

  31. Ricardo SD, van GH, Eddy AA (2008) Macrophage diversity in renal injury and repair. J Clin Invest 118:3522–3530

    PubMed Central  PubMed  CAS  Google Scholar 

  32. Liu L, Kou P, Zeng Q et al (2012) CD4 + T Lymphocytes, especially Th2 cells, contribute to the progress of renal fibrosis. Am J Nephrol 36:386–396

    PubMed  CAS  Google Scholar 

  33. Pindjakova J, Hanley SA, Duffy MM et al (2012) Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction. Kidney Int 81:379–390

    PubMed Central  PubMed  CAS  Google Scholar 

  34. Bige N, Shweke N, Benhassine S et al (2012) Thrombospondin-1 plays a profibrotic and pro-inflammatory role during ureteric obstruction. Kidney Int 81:1226–1238

    PubMed  CAS  Google Scholar 

  35. Gao B, Waisman A (2012) Th17 cells regulate liver fibrosis by targeting multiple cell types: many birds with one stone. Gastroenterology 143:536–539

    PubMed  CAS  Google Scholar 

  36. Tan HL, Regamey N, Brown S, Bush A, Lloyd CM, Davies JC (2011) The Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit Care Med 184:252–258

    PubMed Central  PubMed  CAS  Google Scholar 

  37. Ortiz A, Justo P, Sanz A, Lorz C, Egido J (2003) Targeting apoptosis in acute tubular injury. Biochem Pharmacol 66:1589–1594

    PubMed  CAS  Google Scholar 

  38. Linkermann A, Bräsen JH, Himmerkus N et al (2012) Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int 81:751–761

    PubMed  CAS  Google Scholar 

  39. Sanz AB, Santamaría B, Ruiz-Ortega M, Egido J, Ortiz A (2008) Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol 19:1634–1642

    PubMed  CAS  Google Scholar 

  40. Ardura JA, Berruguete R, Ramila D, Alvarez-Arroyo MV, Esbrit P (2008) Parathyroid hormone-related protein interacts with vascular endothelial growth factor to promote fibrogenesis in the obstructed mouse kidney. Am J Physiol Renal Physiol 295:F415–F425

    PubMed  CAS  Google Scholar 

  41. Ortega A, Rámila D, Ardura JA et al (2006) Role of parathyroid hormone-related protein in tubulointerstitial apoptosis and fibrosis after folic acid-induced nephrotoxicity. J Am Soc Nephrol 17:1594–1603

    PubMed  CAS  Google Scholar 

  42. Degterev A, Huang Z, Boyce M et al (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119

    PubMed  CAS  Google Scholar 

  43. Choi YJ, Baranowska-Daca E, Nguyen V et al (2000) Mechanism of chronic obstructive uropathy: increased expression of apoptosis-promoting molecules. Kidney Int 58:1481–1491

    PubMed  CAS  Google Scholar 

  44. Gobe GC, Axelsen RA (1987) Genesis of renal tubular atrophy in experimental hydronephrosis in the rat Role of apoptosis. Lab Invest 56:273–281

    PubMed  CAS  Google Scholar 

  45. 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 110:341–350

    PubMed Central  PubMed  CAS  Google Scholar 

  46. Humphreys BD, Lin SL, Kobayashi A et al (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176:85–97

    PubMed Central  PubMed  CAS  Google Scholar 

  47. Zeisberg M, Duffield JS (2010) Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 21:1247–1253

    PubMed  Google Scholar 

  48. Misaki T, Yamamoto T, Suzuki S et al (2009) Decrease in tumor necrosis factor-alpha receptor-associated death domain results from ubiquitin-dependent degradation in obstructive renal injury in rats. Am J Pathol 175:74–83

    PubMed Central  PubMed  CAS  Google Scholar 

  49. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV (2010) Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16(535–543):531p

    Google Scholar 

  50. Jones EA, Shahed A, Shoskes DA (2000) Modulation of apoptotic and inflammatory genes by bioflavonoids and angiotensin II inhibition in ureteral obstruction. Urology 56:346–351

    PubMed  CAS  Google Scholar 

  51. Ortiz A, Lorz C, Egido J (1999) The Fas ligand/Fas system in renal injury. Nephrol Dial Transplant 14:1831–1834

    PubMed  CAS  Google Scholar 

  52. Lorz C, Ortiz A, Justo P et al (2000) Proapoptotic Fas ligand is expressed by normal kidney tubular epithelium and injured glomeruli. J Am Soc Nephrol 11:1266–1277

    PubMed  CAS  Google Scholar 

  53. Lange-Sperandio B, Fulda S, Vandewalle A, Chevalier R (2003) Macrophages induce apoptosis in proximal tubule cells. Pediatr Nephrol 18:335–341

    PubMed  Google Scholar 

  54. Grande MT, López-Novoa JM (2009) Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol 5:319–328

    PubMed  CAS  Google Scholar 

  55. Matsuo S, López-Guisa J, Cai X et al (2005) Multifunctionality of PAI-1 in fibrogenesis: evidence from obstructive nephropathy in PAI-1-overexpressing mice. Kidney Int 67:2221–2238

    PubMed  CAS  Google Scholar 

  56. Eddy AA, López-Guisa JM, Okamura DM, Yamaguchi I (2012) Investigating mechanisms of chronic kidney disease in mouse models. Pediatr Nephrol 27:1233–1247

    PubMed Central  PubMed  Google Scholar 

  57. Strutz F, Zeisberg M (2006) Renal fibroblasts and myofibroblast in chronic kidney disease. J Am Soc Nephrol 17:2992–2998

    PubMed  CAS  Google Scholar 

  58. Qi W, Chen X, Poronnik P, Pollock CA (2006) The renal cortical fibroblast in renal tubulointerstitial fibrosis. Int J Biochem Cell Biol 38:1–5

    PubMed  CAS  Google Scholar 

  59. Strutz F (2008) How many different roads may a cell walk down in order to become a fibroblast? J Am Soc Nephrol 19:2246–2248

    PubMed  Google Scholar 

  60. Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173:1617–1627

    PubMed Central  PubMed  CAS  Google Scholar 

  61. Sakai N, Wada T, Yokoyama H et al (2006) Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci USA 103:14098–14103

    PubMed Central  PubMed  CAS  Google Scholar 

  62. Epstein JB, McCarthy GM (1996) Progress in HIV and AIDS care. J Can Dent Assoc 62:866–867

    PubMed  CAS  Google Scholar 

  63. Lee DB, Huang E, Ward HJ (2006) Tight junction biology and kidney dysfunction. Am J Physiol Renal Physiol 290:F20–F34

    PubMed  CAS  Google Scholar 

  64. Sanz AB, Sanchez-Nino MD, Izquierdo MC et al (2010) TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21. PLoS One 5:e8955

    PubMed Central  PubMed  Google Scholar 

  65. Lange-Sperandio B, Trautmann A, Eickelberg O et al (2007) Leukocytes induce epithelial to mesenchymal transition after unilateral ureteral obstruction in neonatal mice. Am J Pathol 171:861–871

    PubMed Central  PubMed  CAS  Google Scholar 

  66. Martinez-Salgado C, Fuentes-Calvo I, Garcia-Cenador B, Santos E, Lopez-Novoa JM (2006) Involvement of H- and N-Ras isoforms in transforming growth factor-beta1-induced proliferation and in collagen and fibronectin synthesis. Exp Cell Res 312:2093–2106

    PubMed  CAS  Google Scholar 

  67. Grande MT, Fuentes-Calvo I, Arevalo M et al (2010) Deletion of H-Ras decreases renal fibrosis and myofibroblast activation following ureteral obstruction in mice. Kidney Int 77:509–518

    PubMed  CAS  Google Scholar 

  68. Bechtel W, McGoohan S, Zeisberg EM et al (2010) Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16:544–550

    PubMed Central  PubMed  CAS  Google Scholar 

  69. Park SJ, Jeong KS (2004) Cell-type-specific activation of mitogen-activated protein kinases in PAN-induced progressive renal disease in rats. Biochem Biophys Res Commun 323:1–8

    PubMed  CAS  Google Scholar 

  70. Pat B, Yang T, Kong C, Watters D, Johnson DW, Gobe G (2005) Activation of ERK in renal fibrosis after unilateral ureteral obstruction: modulation by antioxidants. Kidney Int 67:931–943

    PubMed  CAS  Google Scholar 

  71. Han Y, Masaki T, Hurst LA et al (2008) Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney. Nephrology (Carlton) 13:411–418

    CAS  Google Scholar 

  72. Jin Y, Ratnam K, Chuang PY et al (2012) A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med 18:580–588

    PubMed Central  PubMed  CAS  Google Scholar 

  73. Zhang Y, Kong J, Deb DK, Chang A, Li YC (2010) Vitamin D receptor attenuates renal fibrosis by suppressing the renin-angiotensin system. J Am Soc Nephrol 21:966–973

    PubMed Central  PubMed  CAS  Google Scholar 

  74. Ruiz-Ortega M, Ruperez M, Esteban V et al (2006) Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol Dial Transplant 21:16–20

    PubMed  CAS  Google Scholar 

  75. Wolf G, Mueller E, Stahl RA, Ziyadeh FN (1993) Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta. J Clin Invest 92:1366–1372

    PubMed Central  PubMed  CAS  Google Scholar 

  76. Shin GT, Kim WH, Yim H, Kim MS, Kim H (2005) Effects of suppressing intrarenal angiotensinogen on renal transforming growth factor-beta1 expression in acute ureteral obstruction. Kidney Int 67:897–908

    PubMed  CAS  Google Scholar 

  77. Lavoz C, Rodrigues-Diez R, Benito-Martin A et al (2012) Angiotensin II contributes to renal fibrosis independently of Notch pathway activation. PLoS One 7:e40490

    PubMed Central  PubMed  CAS  Google Scholar 

  78. Fern RJ, Yesko CM, Thornhill BA, Kim HS, Smithies O, Chevalier RL (1999) Reduced angiotensinogen expression attenuates renal interstitial fibrosis in obstructive nephropathy in mice. J Clin Invest 103:39–46

    PubMed Central  PubMed  CAS  Google Scholar 

  79. Ishidoya S, Morrissey J, McCracken R, Reyes A, Klahr S (1995) Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 47:1285–1294

    PubMed  CAS  Google Scholar 

  80. Ishidoya S, Morrissey J, McCracken R, Klahr S (1996) Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy. Kidney Int 49:1110–1119

    PubMed  CAS  Google Scholar 

  81. Klahr S, Ishidoya S, Morrissey J (1995) Role of angiotensin II in the tubulointerstitial fibrosis of obstructive nephropathy. Am J Kidney Dis 26:141–146

    PubMed  CAS  Google Scholar 

  82. Moridaira K, Morrissey J, Fitzgerald M et al (2003) ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction. Am J Physiol Renal Physiol 284:F209–F217

    PubMed  CAS  Google Scholar 

  83. Esteban V, Lorenzo O, Rupérez M et al (2004) Angiotensin II, via AT1 and AT2 receptors and NF-kappaB pathway, regulates the inflammatory response in unilateral ureteral obstruction. J Am Soc Nephrol 15:1514–1529

    PubMed  CAS  Google Scholar 

  84. 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–S14

    PubMed  CAS  Google Scholar 

  85. Satoh M, Kashihara N, Yamasaki Y et al (2001) Renal interstitial fibrosis is reduced in angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol 12:317–325

    PubMed  CAS  Google Scholar 

  86. Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I (1998) Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int 53:937–944

    PubMed  CAS  Google Scholar 

  87. Kaneto H, Morrissey J, McCracken R, Reyes A, Klahr S (1994) Enalapril reduces collagen type IV synthesis and expansion of the interstitium in the obstructed rat kidney. Kidney Int 45:1637–1647

    PubMed  CAS  Google Scholar 

  88. Ferrario CM (2002) Angiotensin I, angiotensin II and their biologically active peptides. J Hypertens 20:805–807

    PubMed  CAS  Google Scholar 

  89. Esteban V, Ruperez M, Sánchez-L¢pez E et al (2005) Angiotensin IV activates the nuclear transcription factor-kappa B and related proinflammatory genes in vascular smooth muscle cells. Circ Res 96:965–973

    PubMed  CAS  Google Scholar 

  90. Esteban V, Heringer-Walther S, Sterner-Kock A et al (2009) Angiotensin-(1–7) and the g protein-coupled receptor MAS are key players in renal inflammation. PLoS One 4:e5406

    PubMed Central  PubMed  Google Scholar 

  91. Tan X, Li Y, Liu Y (2006) Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 17:3382–3393

    PubMed  CAS  Google Scholar 

  92. Miyajima A, Chen J, Lawrence C et al (2000) Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 58:2301–2313

    PubMed  CAS  Google Scholar 

  93. Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A (2003) Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 112:1486–1494

    PubMed Central  PubMed  CAS  Google Scholar 

  94. Inazaki K, Kanamaru Y, Kojima Y et al (2004) Smad3 deficiency attenuates renal fibrosis, inflammation, and apoptosis after unilateral ureteral obstruction. Kidney Int 66:597–604

    PubMed  CAS  Google Scholar 

  95. Lan HY, Mu W, Tomita N et al (2003) Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol 14:1535–1548

    PubMed  CAS  Google Scholar 

  96. Hruska KA, Guo G, Wozniak M et al (2000) Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am J Physiol Renal Physiol 279:F130–F143

    PubMed  CAS  Google Scholar 

  97. Sugiura H, Yoshida T, Shiohira S et al (2012) Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis. Am J Physiol Renal Physiol 302:F1252–F1264

    PubMed  CAS  Google Scholar 

  98. Zhou L, Li Y, Zhou D, Tan RJ, Liu Y (2013) Loss of Klotho Contributes to Kidney Injury by Derepression of Wnt/β-Catenin Signaling. J Am Soc Nephrol 24:771–785

    PubMed  CAS  PubMed Central  Google Scholar 

  99. Satoh M, Nagasu H, Morita Y, Yamaguchi TP, Kanwar YS, Kashihara N (2012) Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. Am J Physiol Renal Physiol 303:F1641–F1651

    PubMed Central  PubMed  CAS  Google Scholar 

  100. Moreno JA, Izquierdo MC, Sanchez-Niño MD et al (2011) The inflammatory cytokines TWEAK and TNFα reduce renal Klotho expression through NFκB. J Am Soc Nephrol 22:1315–1325

    PubMed Central  PubMed  CAS  Google Scholar 

  101. Izquierdo MC, Sanz AB, Sánchez-Niño MD et al (2012) Acute kidney injury transcriptomics unveils a relationship between inflammation and ageing. Nefrologia 32:715–723

    PubMed  Google Scholar 

  102. Izquierdo MC, Perez-Gomez MV, Sanchez-Niño MD et al (2012) Klotho, phosphate and inflammation/ageing in chronic kidney disease. Nephrol Dial Transplant 27(Suppl 4):iv6–iv10

    PubMed  CAS  Google Scholar 

  103. Sugimoto H, Lebleu VS, Bosukonda D et al (2012) Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat Med 18:396–404

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Mazzieri R, Masiero L, Zanetta L et al (1997) Control of type IV collagenase activity by components of the urokinase-plasmin system: a regulatory mechanism with cell-bound reactants. EMBO J 16:2319–2332

    PubMed Central  PubMed  CAS  Google Scholar 

  105. Ishidoya S, Ogata Y, Fukuzaki A, Kaneto H, Takeda A, Orikasa S (2002) Plasminogen activator inhibitor-1 and tissue-type plasminogen activator are up-regulated during unilateral ureteral obstruction in adult rats. J Urol 167:1503–1507

    PubMed  CAS  Google Scholar 

  106. Yang J, Shultz RW, Mars WM et al (2002) Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J Clin Invest 110:1525–1538

    PubMed Central  PubMed  CAS  Google Scholar 

  107. Oda T, Jung YO, Kim HS et al (2001) PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. Kidney Int 60:587–596

    PubMed  CAS  Google Scholar 

  108. Lebleu VS, Teng Y, O’Connell JT et al (2013) Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat Med 19:227–231

    PubMed  CAS  Google Scholar 

  109. Kitagawa K, Wada T, Furuichi K et al (2004) Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol 165:237–246

    PubMed Central  PubMed  CAS  Google Scholar 

  110. Tsou CL, Peters W, Si Y et al (2007) Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest 117:902–909

    PubMed Central  PubMed  CAS  Google Scholar 

  111. Eis V, Luckow B, Vielhauer V et al (2004) Chemokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction. J Am Soc Nephrol 15:337–347

    PubMed  CAS  Google Scholar 

  112. Anders HJ, Vielhauer V, Frink M et al (2002) A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest 109:251–259

    PubMed Central  PubMed  CAS  Google Scholar 

  113. Klein J, Gonzalez J, Duchene J et al (2009) Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy. FASEB J 23:134–142

    PubMed  CAS  Google Scholar 

  114. Miyajima A, Kosaka T, Seta K, Asano T, Umezawa K, Hayakawa M (2003) Novel nuclear factor kappa B activation inhibitor prevents inflammatory injury in unilateral ureteral obstruction. J Urol 169:1559–1563

    PubMed  CAS  Google Scholar 

  115. Kim KH, Lee ES, Cha SH et al (2009) Transcriptional regulation of NF-kappaB by ring type decoy oligodeoxynucleotide in an animal model of nephropathy. Exp Mol Pathol 86:114–120

    PubMed  CAS  Google Scholar 

  116. Ophascharoensuk V, Fero ML, Hughes J, Roberts JM, Shankland SJ (1998) The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury. Nat Med 4:575–580

    PubMed  CAS  Google Scholar 

  117. Hegarty NJ, Young LS, O’Neill AJ, Watson RW, Fitzpatrick JM (2003) Endothelin in unilateral ureteral obstruction: vascular and cellular effects. J Urol 169:740–744

    PubMed  CAS  Google Scholar 

  118. Zhong X, Chung AC, Chen HY, Meng XM, Lan HY (2011) Smad3-mediated upregulation of miR-21 promotes renal fibrosis. J Am Soc Nephrol 22:1668–1681

    PubMed Central  PubMed  CAS  Google Scholar 

  119. Lino Cardenas CL, Henaoui IS, Courcot E et al (2013) miR-199a-5p is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting Caveolin-1. PLoS Genet 9:e1003291

    PubMed Central  PubMed  CAS  Google Scholar 

  120. Chung AC, Huang XR, Meng X, Lan HY (2010) miR-192 mediates TGF-beta/Smad3-driven renal fibrosis. J Am Soc Nephrol 21:1317–1325

    PubMed Central  PubMed  CAS  Google Scholar 

  121. Wang B, Komers R, Carew R et al (2012) Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis. J Am Soc Nephrol 23:252–265

    PubMed Central  PubMed  CAS  Google Scholar 

  122. Qin W, Chung AC, Huang XR et al (2011) TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J Am Soc Nephrol 22:1462–1474

    PubMed Central  PubMed  CAS  Google Scholar 

  123. Chau BN, Xin C, Hartner J, et al. (2012) MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med 4:121ra118

    Google Scholar 

  124. Sanchez-Niño MD, Ortiz A (2012) Notch3 and kidney injury: never two without three. J Pathol 228:266–273

    PubMed  Google Scholar 

  125. Liu N, Guo JK, Pang M et al (2012) Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis. J Am Soc Nephrol 23:854–867

    PubMed Central  PubMed  CAS  Google Scholar 

  126. Bozic M, de Rooij J, Parisi E, Ortega MR, Fernandez E, Valdivielso JM (2011) Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells. J Am Soc Nephrol 22:1099–1111

    PubMed Central  PubMed  CAS  Google Scholar 

  127. Hao S, He W, Li Y et al (2011) Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol 22:1642–1653

    PubMed Central  PubMed  CAS  Google Scholar 

  128. Ophascharoensuk V, Giachelli CM, Gordon K et al (1999) Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int 56:571–580

    PubMed  CAS  Google Scholar 

  129. Zoja C, Corna D, Gagliardini E et al (2010) Adding a statin to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which translates into full renoprotection. Am J Physiol Renal Physiol 299:F1203–F1211

    PubMed  CAS  Google Scholar 

  130. Guo G, Morrissey J, McCracken R, Tolley T, Klahr S (1999) Role of TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive nephropathy. Am J Physiol 277:F766–F772

    PubMed  CAS  Google Scholar 

  131. Kim J, Padanilam BJ (2013) Renal nerves drive interstitial fibrogenesis in obstructive nephropathy. J Am Soc Nephrol 24:229–242

    PubMed Central  PubMed  CAS  Google Scholar 

  132. Ortiz A, Ucero AC, Egido J (2010) Unravelling fibrosis: two newcomers and an old foe. Nephrol Dial Transplant 25:3492–3495

    PubMed  Google Scholar 

  133. El Chaar M, Chen J, Seshan SV et al (2007) Effect of combination therapy with enalapril and the TGF-beta antagonist 1D11 in unilateral ureteral obstruction. Am J Physiol Renal Physiol 292:F1291–F1301

    PubMed  Google Scholar 

  134. Álvarez-Prats A, Hernández-Perera O, Díaz-Herrera P et al (2012) Combination therapy with an angiotensin II receptor blocker and an HMG-CoA reductase inhibitor in experimental subtotal nephrectomy. Nephrol Dial Transplant 27:2720–2733

    PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the following: grant support: FIS 081564, PS09/00447, PI07/0020, CP08/1083, ISCIII-RETIC, REDinREN/RD06/0003, REDin-REN/RD06/0004, FEDER funds, RD12/0021, Comunidad de Madrid/CIFRA S2010/BMD-2378; salary support: FIS to ABM, MDSN, ABS, MCI; FIS and IIS-FJD to AMR; Fundación Conchita Rábago to ACU and SB; Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO.

Author information

Authors and Affiliations

  1. Unidad de Diálisis, IIS-Fundación Jiménez Díaz, Av. Reyes Católicos, 2, 28040, Madrid, Spain

    Alvaro C. Ucero, Alberto Benito-Martin, Maria C. Izquierdo, Ana B. Sanz, Adrian M. Ramos, Sergio Berzal, Marta Ruiz-Ortega, Jesus Egido & Alberto Ortiz

  2. Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 2-4, 28029, Madrid, Spain

    Marta Ruiz-Ortega, Jesus Egido & Alberto Ortiz

  3. IDIPAZ, Paseo de la Castellana, 261, 28046, Madrid, Spain

    Maria D. Sanchez-Niño

  4. Fundación Renal Iñigo Álvarez de Toledo-IRSIN, C/José Abascal, 42, 28003, Madrid, Spain

    Alberto Ortiz

Authors
  1. Alvaro C. Ucero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alberto Benito-Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria C. Izquierdo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria D. Sanchez-Niño
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana B. Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adrian M. Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sergio Berzal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marta Ruiz-Ortega
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jesus Egido
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alberto Ortiz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alberto Ortiz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ucero, A.C., Benito-Martin, A., Izquierdo, M.C. et al. Unilateral ureteral obstruction: beyond obstruction. Int Urol Nephrol 46, 765–776 (2014). https://doi.org/10.1007/s11255-013-0520-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-013-0520-1

Keywords

Search

Navigation