Skip to main content
SpringerLink
Log in

Retinoic acid enhances nephron endowment in rats exposed to maternal protein restriction

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

A reduced nephron complement at birth renders the kidney susceptible to renal disease in adulthood. Retinoic acid (RA; the active metabolite of vitamin A) is linked to nephrogenesis in vitro and in vivo. The aim of this study was to determine the effect of administration of retinoic acid in midgestation in rats on nephron endowment in offspring exposed to maternal protein restriction. Rats were fed either a normal-protein diet (NPD) or a low-protein diet (LPD) during pregnancy and lactation. Half of the dams in the LPD group were injected intraperitoneally with retinoic acid (20 mg/kg) during gestation at embryonic day 11.5. At 4 weeks of age, the offspring were anesthetized and perfusion-fixed, and nephron number estimated using unbiased stereological techniques. Body weight and kidney volume was significantly reduced in all LPD offspring. There was a significant 29% reduction in nephron number in the LPD group compared with the NPD offspring, whereas the number of nephrons in kidneys from the LPD + RA offspring was not significantly different compared with controls. In conclusion, administration of a single bolus dose of retinoic acid during midgestation restored nephron endowment to normal in offspring exposed to maternal protein restriction.

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

References

  1. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME (1989) Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 298:564–567

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ (1989) Weight in infancy and death from ischaemic heart disease. Lancet 2:577–580

    CAS  PubMed  Google Scholar 

  3. Lackland DT, Egan BM, Fan ZL, Syddall HE (2001) Low birth weight contributes to the excess prevalence of end-stage renal disease in African Americans. J Clin Hypertens 3:29–31

    CAS  Google Scholar 

  4. Luyckx VA, Brenner BM (2005) Low birth weight, nephron number and kidney disease. Kidney Int (Suppl) 97:S68–S77

    Google Scholar 

  5. Hoy WE, Rees M, Kile E, Mathews JD, Wang Z (1999) A new dimension to the Barker hypothesis: low birth weight and susceptibility to renal disease. Kidney Int 56:1072–1077

    CAS  PubMed  Google Scholar 

  6. Thomas M (2005) Deprivation and dialysis: pathways to kidney failure in Australian Aborigines. Adv Chronic Kidney Dis 12:84–87

    PubMed  Google Scholar 

  7. Goldstein RS, Hook JB, Bond JT (1979) The effects of maternal protein deprivation on renal development and function in neonatal rats. J Nutr 109:949–957

    CAS  PubMed  Google Scholar 

  8. Merlet-Benichou C, Gilbert T, Muffat-Joly M, Lelievre-Pegorier M, Leroy B (1994) Intrauterine growth retardation leads to a permanent nephron deficit in the rat. Pediatr Nephrol 8:175–180

    CAS  PubMed  Google Scholar 

  9. Langley-Evans SC, Welham SJ, Sherman RC, Jackson AA (1996) Weanling rats exposed to maternal low-protein diets during discrete periods of gestation exhibit differing severity of hypertension. Clin Sci 91:607–615

    CAS  PubMed  Google Scholar 

  10. Langley-Evans SC (1997) Maternal carbenoxolone treatment lowers birthweight and induces hypertension in the offspring of rats fed a protein-replete diet. Clin Sci 93:423–429

    CAS  PubMed  Google Scholar 

  11. Allen LH, Zeman FJ (1973) Influence of increased postnatal nutrient intake on kidney cellular development in progeny of protein-deficient rats. J Nutr 103:929–936

    CAS  PubMed  Google Scholar 

  12. Hinchliffe SA, Lynch MR, Sargent PH, Howard CV, Van Velzen D (1992) The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol 99:296–301

    CAS  PubMed  Google Scholar 

  13. Merlet-Benichou C, Vilar J, Lelievre-Pegorier M, Moreau E, Gilbert T (1997) Fetal nephron mass: its control and deficit. Adv Nephrol Necker Hosp 26:19–45

    CAS  PubMed  Google Scholar 

  14. Hinchliffe SA, Sargent PH, Howard CV, Chan YF, Van Velzen D (1991) Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Invest 64:777–784

    CAS  PubMed  Google Scholar 

  15. Larsson L, Aperia A, Wilton P (1980) Effect of normal development on compensatory renal growth. Kidney Int 18:29–35

    CAS  PubMed  Google Scholar 

  16. Zimanyi MA, Bertram JF, Black MJ (2000) Nephron number in the offspring of rats fed a low protein diet during pregnancy. Image Anal Stereol 19:219–222

    CAS  Google Scholar 

  17. Langley-Evans SC, Welham SJ, Jackson AA (1999) Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci 64:965–974

    CAS  PubMed  Google Scholar 

  18. Gilbert JS, Lang AL, Grant AR, Nijland MJ (2005) Maternal nutrient restriction in sheep: hypertension and decreased nephron number in offspring at 9 months of age. J Physiol 565:137–147

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Brenner BM, Garcia DL, Anderson S (1988) Glomeruli and blood pressure: less of one, more of the other? Am J Hypertens 1:335–347

    CAS  PubMed  Google Scholar 

  20. Black MJ, Briscoe TA, Constantinou M, Kett MM, Bertram JF (2004) Is there an association between level of adult blood pressure and nephron number or renal filtration surface area? Kidney Int 65:582–588

    PubMed  Google Scholar 

  21. Zimanyi MA, Bertram JF, Black MJ (2004) Does a nephron deficit in rats predispose to salt-sensitive hypertension? Kidney Blood Press Res 27:239–247

    PubMed  Google Scholar 

  22. Zimanyi MA, Denton KM, Forbes JM, Thallas-Bonke V, Thomas MC, Poon F, Black MJ (2006) Developmental nephron deficit is associated with increased susceptibility to secondary renal injury due to advanced glycation end-products (AGEs). Diabetologia 49:801–810

    CAS  PubMed  Google Scholar 

  23. Plank C, Ostreicher I, Hartner A, Marek I, Struwe FG, Amann K, Hilgers KF, Rascher W, Dotsch J (2006) Intrauterine growth retardation aggravates the course of acute mesangioproliferative glomerulonephritis in the rat. Kidney Int 70:1974–1988

    CAS  PubMed  Google Scholar 

  24. Vilar J, Gilbert T, Moreau E, Merlet-Benichou C (1996) Metanephros organogenesis is highly stimulated by vitamin A derivatives in organ culture. Kidney Int 49:1478–1487

    CAS  PubMed  Google Scholar 

  25. Lelievre-Pegorier M, Vilar J, Ferrier M-L, Moreau E, Freund N, Gilbert T, Merlet-Benichou C (1998) Mild vitamin A deficiency leads to inborn nephron deficit in the rat. Kidney Int 54:1455–1462

    CAS  PubMed  Google Scholar 

  26. Moreau E, Vilar J, Lelievre-Pegorier M, Merlet-Benichou C, Gilbert T (1998) Regulation of c-ret expression by retinoic acid in rat metanephros: implication in nephron mass control. Am J Physiol 275:F938–F945

    CAS  PubMed  Google Scholar 

  27. Mendelsohn C, Batourina E, Fung S, Gilbert T, Dodd J (1999) Stromal cells mediate retinoid-dependent functions essential for renal development. Development 126:1139–1148

    CAS  PubMed  Google Scholar 

  28. Gilbert T, Merlet-Benichou C (2000) Retinoids and nephron mass control. Pediatr Nephrol 14:1137–1144

    CAS  PubMed  Google Scholar 

  29. Batourina E, Gim S, Bello N, Shy M, Clagett-Dame M, Srinivas S, Costantini F, Mendelsohn C (2001) Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Nat Genet 27:74–78

    CAS  PubMed  Google Scholar 

  30. Vehaskari VM, Aviles DH, Manning J (2001) Prenatal programming of adult hypertension in the rat. Kidney Int 59:238–245

    CAS  PubMed  Google Scholar 

  31. Neugarten J, Kasiske B, Silbiger SR, Nyengaard JR (2002) Effects of sex on renal structure. Nephron 90:139–144

    PubMed  Google Scholar 

  32. Brandt Corstius H, Zimanyi MA, Maka N, Herath T, Thomas W, van der Laarse A, Wreford NG, Black MJ (2005) Effect of intrauterine growth restriction on the number of cardiomyocytes in rat hearts. Pediatr Res 57:796–800

    Google Scholar 

  33. Wilson JG, Roth CB, Warkany J (1953) An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 92:189–217

    CAS  PubMed  Google Scholar 

  34. Campbell JL Jr, Smith MA, Fisher JW, Warren DA (2004) Dose-response for retinoic acid-induced forelimb malformations and cleft palate: a comparison of computerised image analysis and visual inspection. Birth Defects Res B Dev Reprod Toxicol 71:289–295

    CAS  PubMed  Google Scholar 

  35. Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sorrensen FB, Vesterby A, West MJ (1988) Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379–394

    CAS  PubMed  Google Scholar 

  36. Black MJ, Briscoe TA, Dunstan HJ, Bertram JF, Johnston CI (2001) Effect of angiotensin-converting enzyme inhibition on renal filtration surface area in hypertensive rats. Kidney Int 60:1837–1843

    CAS  PubMed  Google Scholar 

  37. Gubhaju L, Black MJ (2005) The baboon as a good model for studies of human kidney development. Pediatr Res 58:505–509

    PubMed  Google Scholar 

  38. Nyengaard JR, Bendtsen TF (1992) Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 232:194–201

    CAS  PubMed  Google Scholar 

  39. Saxen L (1987) Organogenesis of the kidney. Cambridge University Press, Cambridge, pp 1–34

    Google Scholar 

  40. Moritz KM, Wintour EM (1999) Functional development of the meso-and metanephros. Pediatr Nephrol 13:171–178

    CAS  PubMed  Google Scholar 

  41. Kuure S, Vuolteenaho R, Vainio S (2000) Kidney morphogenesis: cellular and molecular regulation. Mech Dev 92:31–45

    CAS  PubMed  Google Scholar 

  42. Vega QC, Worby CA, Lechner MS, Dixon JE, Dressler GR (1996) Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc Natl Acad Sci USA 93:10657–10661

    CAS  PubMed  Google Scholar 

  43. Sainio K, Suvanto P, Davies J, Wartiovaara J, Wartiovaara K, Saarma M, Arumae U, Meng X, Lindahl M, Pachnis V, Sariola H (1997) Glial-cell-line-derived neurotrophic factor is required for bud initiation from ureteric epithelium. Development 124:4077–4087

    CAS  PubMed  Google Scholar 

  44. Welham SJ, Wade A, Woolf AS (2002) Protein restriction in pregnancy is associated with increased apoptosis of mesenchymal cells at the start of rat metanephrogenesis. Kidney Int 61:1231–1242

    CAS  PubMed  Google Scholar 

  45. Wintour EM, Moritz KM, Johnson K, Ricardo S, Samuel CS, Dodic M (2003) Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol 549:929–935

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wintour EM, Alcorn D, Butkus A, Congiu M, Earnest L, Pompolo S, Potocnik SJ (1996) Ontogeny of hormonal and excretory function of the meso-and metanephros in the ovine fetus. Kidney Int 50:1624–1633

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy & Cell Biology, Monash University, Post Office Box 13C, Melbourne, VIC, 3800, Australia

    John Makrakis, Monika A. Zimanyi & M. Jane Black

Authors
  1. John Makrakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monika A. Zimanyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Jane Black
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Jane Black.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Makrakis, J., Zimanyi, M.A. & Black, M.J. Retinoic acid enhances nephron endowment in rats exposed to maternal protein restriction. Pediatr Nephrol 22, 1861–1867 (2007). https://doi.org/10.1007/s00467-007-0572-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-007-0572-5

Keywords

Search

Navigation