Mechanisms of renal ageing in a rodent model of developmental programming arising from early catch-up growth

Abstract

This thesis examines the underlying mechanisms of how in utero growth restriction (IUGR), followed by postnatal catch-up growth, predisposes the offspring to accelerated renal ageing. Advanced renal ageing following in utero nutritional deprivation has been indicated in large population cohort studies, such as the Dutch Hunger Winter or the Leningrad Siege. To address potential mechanisms contributing to accelerated renal ageing, an established rodent model was used in which IUGR is achieved by dietary protein restriction in pregnant Wistar rats. An enhanced nutritional plane after IUGR has been shown to be particularly detrimental to offspring metabolism. To enhance post-natal overfeeding, the offspring were suckled by control dams and also reduced to 4 (males) per litter known as recuperated animals). To investigate the potential role of hypertension and vascular dysfunction, blood pressure was measured in vivo in 3 month old offspring, using radio telemetry, and vascular function was assessed in renal and peripheral resistance arteries in vitro on a wire myograph. No differences between control and recuperated groups were found although control blood pressure was higher and endothelium dependent relaxation impaired compared to historic controls. There was no evidence of enhanced sympathetic activation in the recuperated group. As mitochondrial dysfunction has previously been implicated, renal mitochondrial function in 3 month old animals we determined whether dietary supplementation coenzyme Q10 (CoQ) could restore renal mitochondrial function, however CoQ had a detrimental effect and did not restore activity. Renal function was assessed by measuring proteinuria, creatinine clearance and plasma renin. Renal morphology and inflammation were assessed by electron microscopy, ED-1, CD-3 and a periodic acid schiff (PAS) stain. There were no signs of early programmed differences in renal function. Enhanced renin gene and protein expression in recuperated animals at 3 months did suggest alterations in renin-angiotensin system (RAS) activity. Accelerated renal ageing in offspring of IUGR rats followed by catch up growth is not due to raised blood pressure or vascular dysfunction and is not reversible with an antioxidant strategy at 3 months of age.

Date of Award	2016
Original language	English
Awarding Institution	King's College London
Supervisor	Lucilla Poston (Supervisor) & Paul Taylor (Supervisor)