Role of postnatal dietary sodium in prenatally programmed hypertension


In this study we examined the short- and long-term impact of early life dietary sodium (Na) on prenatally programmed hypertension. Hypertension was induced in rat offspring by a maternal low protein (LP) diet. Control and LP offspring were randomized to a high (HS), standard (SS), or low (LS) Na diet after weaning. On the SS diet, the LP pups developed hypertension by 6 weeks of age. The development of hypertension was prevented by the LS diet and exacerbated by the HS diet. Kidney nitrotyrosine content, a measure of oxidative stress, was reduced by the LS diet compared with the HS diet. The modified diets had no effect on control pups. A group of animals on the SS diet was followed up to 51 weeks of age after an early life 3-week exposure to the HS or LS diet. This brief early exposure of LP animals to the LS diet prevented the later development of hypertension and ameliorated the nephrosclerosis observed after early exposure to the HS diet. The LP offspring with early exposure to LS diet had lost their salt-sensitivity when challenged with the HS diet at the age of 43–49 weeks. No effect of early life dietary Na was observed in control animals. These results show that hypertension in this model is salt sensitive and may, in part, be mediated by salt-induced renal oxidative stress and that there may exist a developmental window which allows postnatal “reprogramming” of the hypertension.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ (1989) Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Br Med J 298:564–567

    CAS  Article  Google Scholar 

  2. 2.

    Curhan GC, Chertow GM, Willett WC, Spiegelman D, Colditz GA, Manson J, Speizer FE, Stampfer MJ (1996) Birth weight and adult hypertension and obesity in women. Circulation 94:1310–1315

    CAS  Article  Google Scholar 

  3. 3.

    Law CM, Shiell AW (1996) Is blood pressure inversely related to birth weight? The strength of evidence from systematic review of the literature. J Hypertens 14:935–941

    CAS  Article  Google Scholar 

  4. 4.

    Levitt NS, Lambert EV, Woods D, Hales CN, Andrew R, Seckl JR (2000) Impaired glucose tolerance and elevated blood pressure in low birth weight, nonobese, young South African adults: early programming of cortisol axis. J Clin Endocrin Metab 85:4611–4618

    CAS  Google Scholar 

  5. 5.

    Langley-Evans SC, Welham SJM, 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  Article  Google Scholar 

  6. 6.

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

    CAS  Article  Google Scholar 

  7. 7.

    Woods LL, Weeks DA, Rasch R (2004) Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Int 65:1339–1348

    Article  Google Scholar 

  8. 8.

    Ortiz LA, Quan A, Zarzar F, Weinberg A, Baum M (2003) Prenatal dexamethasone programs hypertension and renal injury in the rat. Hypertension 41:328–334

    CAS  Article  Google Scholar 

  9. 9.

    Alexander BT (2003) Placental insufficiency leads to development of hypertension in growth-restricted offspring. Hypertension 41:457–462

    CAS  Article  Google Scholar 

  10. 10.

    Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359:61–73

    CAS  Article  Google Scholar 

  11. 11.

    Benediktsson R, Linsay R, Noble J, Seckl JR, Edwards CR (1993) Glucocorticoid exposure in utero: a new model for adult hypertension. Lancet 341:339–341

    CAS  Article  Google Scholar 

  12. 12.

    Vehaskari VM, Woods LL (2005) Prenatally programmed hypertension: Lessons from experimental models. J Am Soc Nephrol 16:2545–2556

    CAS  Article  Google Scholar 

  13. 13.

    Guyton AC, Coleman RG, Cowley AW Jr, Scheel KW, Manning RD Jr, Norman RA Jr (1972) Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med 52:584–594

    CAS  PubMed  Google Scholar 

  14. 14.

    Keller G, Zimmer G, Mall G, Ritz E, Amann K (2003) Nephron number in patients with primary hypertension. N Engl J Med 348:101–108

    Article  Google Scholar 

  15. 15.

    Manning J, Buetler K, Knepper MA, Vehaskari VM (2002) Upregulation of BSC1 and TSC in prenatally programmed hypertension. Am J Physiol 283:F202–F206

    CAS  Google Scholar 

  16. 16.

    Dagan A, Gattineni J, Cook V, Baum M (2007) Prenatal programming of rat proximal tubule Na+/H+ exchanger by dexamethasone. Am J Physiol 292:R1230–R1235

    CAS  Google Scholar 

  17. 17.

    Manning J, Vehaskari VM (2005) Postnatal modulation of prenatally programmed hypertension by dietary Na and ACE inhibition. Am J Physiol 288:R80–R84

    CAS  Google Scholar 

  18. 18.

    Stewart T, Jung FF, Manning J, Vehaskari VM (2005) Kidney immune cell infiltration and oxidative stress contribute to prenatally programmed hypertension. Kidney Int 68:2180–2188

    CAS  Article  Google Scholar 

  19. 19.

    Rodriguez-Iturbe B, Vaziri ND, Herrera-Acosta J, Johnson RJ (2004) Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all. Am J Physiol 286:F606–F616

    CAS  Google Scholar 

  20. 20.

    Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B (2002) Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 346:913–923

    CAS  Article  Google Scholar 

  21. 21.

    Vaziri ND, Rodriguez-Iturbe B (2006) Mechanisms of disease: oxidative stress and inflammation in the pathogenesis of hypertension. Nat Clin Pract Nephrol 10:582–593

    Article  Google Scholar 

  22. 22.

    Wilcox CS (2005) Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol 289:R913–R935

    CAS  Google Scholar 

  23. 23.

    Taylor NE, Glocka P, Liang M, Cowley AW Jr (2006) NADPH oxidase in the renal medulla causes oxidative stress and contributes to salt-sensitive hypertension in Dahl S rats. Hypertension 47:692–698

    CAS  Article  Google Scholar 

  24. 24.

    Rodriguez-Iturbe B, Sepassi L, Quiroz Y, Ni Z, Vaziri ND (2007) Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence. J Appl Physiol 102:255–260

    CAS  Article  Google Scholar 

  25. 25.

    Kitiyakara C, Chabrashvili T, Chen Y, Blau J, Karber A, Aslam S, Welch WJ, Wilcox CS (2003) Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. J Am Soc Nephrol 14:2775–2782

    CAS  Article  Google Scholar 

  26. 26.

    Chandramohan G, Bai Y, Norris K, Rodriguez-Iturbe, Vaziri ND (2008) Effects of dietary salt on intrarenal angiotensin system NAD(P)H oxidase, COX-2, MCP-1 and PAI-1 expressions and NF-κB activity in salt-sensitive and –resistant rat kidneys. Am J Nephrol 28:158-167

  27. 27.

    Vehaskari VM (2007) Developmental origins of adult hypertension: new insights into the role of the kidney. Pediatr Nephrol 22:490–495

    Article  Google Scholar 

  28. 28.

    Vaziri ND, Bai Y, Ni Z, Quiroz Y, Pandian R, Rodriguez-Iturbe B (2007) Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass production. J Pharmacol Exp Ther 323:85–93

    CAS  Article  Google Scholar 

  29. 29.

    Johnson RJ, Feig DI, Nakagawa T, Sanchez-Lozada LG, Rodriguez-Iturbe B (2008) Pathogenesis of essential hypertension: historical paradigms and modern insights. J Hypertens 26:381–391

    CAS  Article  Google Scholar 

  30. 30.

    Vehaskari VM, Stewart T, Lafont D, Soyez C, Seth D, Manning J (2004) Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am J Physiol 287:F262–F267

    CAS  Google Scholar 

  31. 31.

    Franco M, Martinez F, Quiroz Y, Galicia O, Bautista R, Johnson RJ, Rodriguez-Iturbe B (2007) Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension. Am J Physiol 293:R251–R256

    CAS  Google Scholar 

  32. 32.

    Carlstrom M, Sallstrom J, Skott O, Larsson E, Persson AE (2007) Uninephrectomy in young age or chronic salt loading causes salt-sensitive hypertension in adult rats. Hypertension 49:1342–1350

    Article  Google Scholar 

  33. 33.

    Lundie MJ, Friberg P, Kline RL, Adams MA (1997) Long-term inhibition of the renin-angiotensin system in genetic hypertension: analysis of the impact on blood pressure and cardiovascular structural changes. J Hypertens 15:339–348

    CAS  Article  Google Scholar 

  34. 34.

    Racasan S, Hahnel B, van der Giezen D, Blezer EL, Goldenschmeding R, Braam B, Kritz W, Koomans HA, Joles JA (2004) Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension. Kidney Int 65:575–581

    CAS  Article  Google Scholar 

  35. 35.

    Ishiguro K, Sasamura H, Sakamaki Y, Itoh H, Saruta T (2007) Developmental activity of the renin-angiotensin system during the ”critical period” modulates later L-NAME-induced hypertension and renal injury. Hypertens Res 30:63–75

    CAS  Article  Google Scholar 

Download references


Support for this study was provided by National Heart, Lung, and Blood Institute Grant RO1 HL66158. This paper was presented in part as an abstract at the Annual Meeting of the American Society of Nephrology in November 2007.

Author information



Corresponding author

Correspondence to V. Matti Vehaskari.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stewart, T., Ascani, J., Craver, R.D. et al. Role of postnatal dietary sodium in prenatally programmed hypertension. Pediatr Nephrol 24, 1727–1733 (2009).

Download citation


  • Developmental origins
  • Oxidative stress
  • Salt-sensitivity
  • Tubulointerstitial injury