Increased cardiovascular and renal risk is associated with low nephron endowment in aged females: an ovine model of fetal unilateral nephrectomy

PLoS One. 2012;7(8):e42400. doi: 10.1371/journal.pone.0042400. Epub 2012 Aug 3.

Abstract

Previously we have shown that ovariectomised (OVX) female sheep have reduced renal function and elevated blood pressure from 6 months of age following fetal uninephrectomy (uni-x) at 100 days of gestation (term = 150 days). In the current study we examined if in intact female sheep the onset of decline in renal function and elevation in blood pressure was prevented. Studies were performed at 1 year, 2 and 5 years of age. Following fetal uni-x at 100 days, intact female sheep had ~30% reduction in glomerular filtration rate (GFR) at 1 year, which did not exacerbate with age (P(treatment) = 0.0001, P(age) = 0.7). In contrast renal blood flow was similar between the treatment groups at 1 year of age but had declined in the uni-x animals at 5 years of age (P(treatment × age) = 0.046). Interestingly, intact uni-x sheep did not develop elevations in arterial pressure until 2 years of age. Furthermore, uni-x animals had a similar capacity to respond to a cardiac challenge at 1 year and 2 years of age, however, cardiac functional reserve was significantly reduced compared to sham group at 5 years of age. Uni-x animals exhibited an increase in left ventricular dimensions at 5 years of age compared to the sham animals and compared to 2 years of age (P(treatment)<0.001, P(treatment × age)<0.001). In conclusion, the onset of renal dysfunction preceded the onset of hypertension in intact female uni-x sheep. Furthermore, this study showed that the intact females are protected from the impact of a reduced nephron endowment on cardiovascular health early in life as opposed to our findings in young male sheep and OVX uni-x female sheep. However, with ageing this protection is lost as evidenced by presence of left ventricular hypertrophy and impaired cardiac function in 5 year old uni-x female sheep.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Arterial Pressure / physiology
  • Birth Weight / drug effects
  • Cardiovascular Physiological Phenomena* / drug effects
  • Collagen / metabolism
  • Dobutamine / pharmacology
  • Echocardiography
  • Female
  • Fetus / surgery*
  • Gene Expression Regulation, Developmental / drug effects
  • Heart Function Tests
  • Heart Rate / physiology
  • Hormones / blood
  • Ions / blood
  • Kidney / physiology
  • Kidney / surgery*
  • Kidney Function Tests
  • Models, Animal
  • Nephrectomy*
  • Nephrons / drug effects
  • Nephrons / physiology*
  • Renin / blood
  • Risk Factors
  • Sheep / blood
  • Sheep / growth & development
  • Sheep / surgery*
  • Time Factors

Substances

  • Hormones
  • Ions
  • Dobutamine
  • Collagen
  • Renin

Grants and funding

This project was supported by a National Heart Foundation Grant (G 05M 2110) and Monash University Research Fund. RS was supported by an Australian Postgraduate Award and Monash University, Faculty of Medicine, Nursing and Health Sciences Bridging Post-Doctoral Fellowship. KM was supported by an National Health and Medical Research Council (NHMRC) Career Development Award and by an (NHMRC) Senior Research Fellowship and KD was supported by an NHMRC Senior Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.