Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지
DOI QR코드

DOI QR Code

Impaired angiogenesis in the enalapril-treated neonatal rat kidney

  • Yim, Hyung Eun (Department of Pediatrics, Korea University College of Medicine) ;
  • Yoo, Kee Hwan (Department of Pediatrics, Korea University College of Medicine) ;
  • Bae, Eun Soo (Department of Pediatrics, Korea University College of Medicine) ;
  • Hong, Young Sook (Department of Pediatrics, Korea University College of Medicine) ;
  • Lee, Joo Won (Department of Pediatrics, Korea University College of Medicine)
  • Received : 2015.03.09
  • Accepted : 2015.06.13
  • Published : 2016.01.10
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Nephrogenesis is normally accompanied by a tightly regulated and efficient vascularization. We investigated the effect of angiotensin II inhibition on angiogenesis in the developing rat kidney. Methods: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle (control) for 7 days after birth. Renal histological changes were checked using Hematoxylin & Eosin staining. We also investigated the intrarenal expression of vascular endothelial growth factor (VEGF)-A, VEGF receptor 1 (VEGFR1), VEGFR2, platelet-derived growth factor (PDGF)-B, and PDGF receptor-${\beta}$ with Western blotting and immunohistochemical staining at postnatal day 8. Expression of the endothelial cell marker CD31 was examined to determine glomerular and peritubular capillary density. Results: Enalapril-treated rat kidneys showed disrupted tubules and vessels when compared with the control rat kidneys. In the enalapril-treated group, intrarenal VEGF-A protein expression was significantly higher, whereas VEGFR1 protein expression was lower than that in the control group (P<0.05). The expression of VEGFR2, PDGF-B, and PDGF receptor-${\beta}$ was not different between the 2 groups. The increased capillary CD31 expression on the western blots of enalapril-treated rat kidneys indicated that the total endothelial cell protein level was increased, while the cortical capillary density, assessed using CD31 immunohistochemical staining, was decreased. Conclusion: Impaired VEGF-VEGFR signaling and altered capillary repair may play a role in the deterioration of the kidney vasculature after blocking of angiotensin II during renal development.

Keywords

References

  1. Guron G, Friberg P. An intact renin-angiotensin system is a prerequisite for normal renal development. J Hypertens 2000;18:123-37. https://doi.org/10.1097/00004872-200018020-00001
  2. Sequeira Lopez ML, Gomez RA. Development of the renal arterioles. J Am Soc Nephrol 2011;22:2156-65. https://doi.org/10.1681/ASN.2011080818
  3. Yim HE, Kim MK, Bae IS, Kim JH, Choi BM, Yoo KH, et al. AT1 antagonist modulates activin-like kinase 5 and TGF-beta receptor II in the developing kidney. Pediatr Nephrol 2006;21:1377-88. https://doi.org/10.1007/s00467-006-0197-0
  4. Gomez RA, Lynch KR, Chevalier RL, Everett AD, Johns DW, Wilfong N, et al. Renin and angiotensinogen gene expression and intrarenal renin distribution during ACE inhibition. Am J Physiol 1988;254(6 Pt 2):F900-6.
  5. Tufro-McReddie A, Romano LM, Harris JM, Ferder L, Gomez RA. Angiotensin II regulates nephrogenesis and renal vascular development. Am J Physiol 1995;269(1 Pt 2):F110-5. https://doi.org/10.1152/ajpcell.1995.269.1.C110
  6. Gomez RA. Role of angiotensin in renal vascular development. Kidney Int Suppl 1998;67:S12-6.
  7. Friberg P, Sundelin B, Bohman SO, Bobik A, Nilsson H, Wickman A, et al. Renin-angiotensin system in neonatal rats: induction of a renal abnormality in response to ACE inhibition or angiotensin II antagonism. Kidney Int 1994;45:485-92. https://doi.org/10.1038/ki.1994.63
  8. Guron G, Adams MA, Sundelin B, Friberg P. Neonatal angiotensin-converting enzyme inhibition in the rat induces persistent abnormalities in renal function and histology. Hypertension 1997;29(1 Pt 1):91-7. https://doi.org/10.1161/01.HYP.29.1.91
  9. Eardley KS, Kubal C, Zehnder D, Quinkler M, Lepenies J, Savage CO, et al. The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease. Kidney Int 2008;74:495-504. https://doi.org/10.1038/ki.2008.183
  10. Mallamaci F, Benedetto FA, Tripepi G, Cutrupi S, Pizzini P, Stancanelli B, et al. Vascular endothelial growth factor, left ventricular dysfunction and mortality in hemodialysis patients. J Hypertens 2008;26:1875-82. https://doi.org/10.1097/HJH.0b013e328307c3d2
  11. Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, et al. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 2002;13:806-16.
  12. Kida Y, Tchao BN, Yamaguchi I. Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease. Pediatr Nephrol 2014;29:333-42. https://doi.org/10.1007/s00467-013-2430-y
  13. Lin SL, Chang FC, Schrimpf C, Chen YT, Wu CF, Wu VC, et al. Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol 2011;178:911-23. https://doi.org/10.1016/j.ajpath.2010.10.012
  14. Ribatti D, Nico B, Crivellato E. The role of pericytes in angiogenesis. Int J Dev Biol 2011;55:261-8. https://doi.org/10.1387/ijdb.103167dr
  15. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003; 111:707-16. https://doi.org/10.1172/JCI17423
  16. Darland DC, Massingham LJ, Smith SR, Piek E, Saint-Geniez M, D'Amore PA. Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 2003;264:275-88. https://doi.org/10.1016/j.ydbio.2003.08.015
  17. Evensen L, Micklem DR, Blois A, Berge SV, Aarsaether N, Littlewood-Evans A, et al. Mural cell associated VEGF is required for organotypic vessel formation. PLoS One 2009;4:e5798. https://doi.org/10.1371/journal.pone.0005798
  18. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358:1129-36. https://doi.org/10.1056/NEJMoa0707330
  19. Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 2006;39:469-78.
  20. Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 2003;17:1835-40. https://doi.org/10.1101/gad.266803
  21. Walther T, Menrad A, Orzechowski HD, Siemeister G, Paul M, Schirner M. Differential regulation of in vivo angiogenesis by angiotensin II receptors. FASEB J 2003;17:2061-7. https://doi.org/10.1096/fj.03-0129com
  22. Zhang X, Lassila M, Cooper ME, Cao Z. Retinal expression of vascular endothelial growth factor is mediated by angiotensin type 1 and type 2 receptors. Hypertension 2004;43:276-81. https://doi.org/10.1161/01.HYP.0000113628.94574.0f
  23. Lombardi D, Gordon KL, Polinsky P, Suga S, Schwartz SM, Johnson RJ. Salt-sensitive hypertension develops after short-term exposure to Angiotensin II. Hypertension 1999;33:1013-9. https://doi.org/10.1161/01.HYP.33.4.1013
  24. Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 2004;66:496-9. https://doi.org/10.1111/j.1523-1755.2004.761_5.x
  25. Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL, et al. Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. J Am Soc Nephrol 2001;12:1434-47.
  26. Ohashi R, Kitamura H, Yamanaka N. Peritubular capillary injury during the progression of experimental glomerulonephritis in rats. J Am Soc Nephrol 2000;11:47-56.
  27. Sato W, Tanabe K, Kosugi T, Hudkins K, Lanaspa MA, Zhang L, et al. Selective stimulation of VEGFR2 accelerates progressive renal disease. Am J Pathol 2011;179:155-66. https://doi.org/10.1016/j.ajpath.2011.03.024
  28. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995;376:66-70. https://doi.org/10.1038/376066a0
  29. Sato W, Kosugi T, Zhang L, Roncal CA, Heinig M, Campbell-Thompson M, et al. The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy. Lab Invest 2008;88:949-61. https://doi.org/10.1038/labinvest.2008.60
  30. Shih SC, Ju M, Liu N, Smith LE. Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 2003;112:50-7. https://doi.org/10.1172/JCI17808
  31. Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 2006;312:549-60. https://doi.org/10.1016/j.yexcr.2005.11.012
  32. Sison K, Eremina V, Baelde H, Min W, Hirashima M, Fantus IG, et al. Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling. J Am Soc Nephrol 2010;21: 1691-701. https://doi.org/10.1681/ASN.2010030295
  33. Kuhnert F, Tam BY, Sennino B, Gray JT, Yuan J, Jocson A, et al. Soluble receptor-mediated selective inhibition of VEGFR and PDGFRbeta signaling during physiologic and tumor angiogenesis. Proc Natl Acad Sci U S A 2008;105:10185-90. https://doi.org/10.1073/pnas.0803194105
  34. Zhang J, Cao R, Zhang Y, Jia T, Cao Y, Wahlberg E. Differential roles of PDGFR-alpha and PDGFR-beta in angiogenesis and vessel stability. FASEB J 2009;23:153-63. https://doi.org/10.1096/fj.08-113860
  35. Futrakul N, Butthep P, Futrakul P. Altered vascular homeostasis in chronic kidney disease. Clin Hemorheol Microcirc 2008;38:201-7.

Cited by

  1. Capillary rarefaction and altered renal development: the imbalance between pro- and anti-angiogenic factors in response to angiotensin II inhibition in the developing rat kidney vol.49, pp.2, 2018, https://doi.org/10.1007/s10735-018-9762-7
  2. Angiotensin inhibition in the developing kidney; tubulointerstitial effect vol.85, pp.5, 2016, https://doi.org/10.1038/s41390-019-0288-9
  3. Angiotensin inhibition and cellular senescence in the developing rat kidney vol.117, pp.None, 2016, https://doi.org/10.1016/j.yexmp.2020.104551