Abstract 452: The Degree of Nephron Deficit is a Determinant of the Cardiovascular and Renal Risks Associated With a Reduced Nephron Endowment

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Abstract

A reduced nephron endowment is associated with an increased sensitivity to hypertensive stimuli. We examined whether nephron endowment, and the degree of nephron deficit, impacts on the blood pressure and renal response to chronic angiotensin II (AngII) infusion. To address this aim we used the GDNF heterozygous mouse that, despite the same genotype, produces two distinct levels of nephron deficit due to the role of GDNF in both the initiation of kidney development and induction of nephron formation. GDNF het mice are born with either 2 small kidneys and a 30% nephron deficit (Het2K), or a single small kidney (Het1K) and a 65% nephron deficit compared to wild-type littermates (WT).

Sixteen week old male GDNF WT (n=9), Het2K (n=5) and Het1K (n=7) mice were implanted with radiotelemetry probes and baseline pressures recorded. Mice were administered enalapril (10mg/kg/day, drinking water) alone for 3 days, then concomitant with an AngII infusion (600ng/kg/min; s.c. osmotic minipump) for a further 21 days. 24hr albumin and urine excretion were assessed at baseline and at the end of the 21 days of blood pressure recording.

Baseline MAP was not different between WT, Het2K and Het1K groups (98.3±1.3, 97.1±1.8, 100.9±1.9mmHg respectively). Enalapril treatment led to a similar fall in MAP of 23mmHg in the 3 groups before the commencement of AngII infusion. AngII led to an immediate rise in MAP in all groups. At the end of the 21day infusion period, MAP of WT and Het2K mice were similar (122±3.3, 120.5±6.1mmHg), but MAP of Het1K mice (139.7±3.6mmHg; P<0.01) was significantly elevated over WT mice. Albumin excretion was not different between the groups at baseline, and AngII infusion did not significantly increase albumin excretion in WT or Het2K mice. However albumin excretion in Het1K mice increased 15 fold (4.86±1.56 to 76.05±30.3ug/24hr; P<0.001). Urine excretion also significantly increased in the Het1K (1.59±1.5 to 3.7±0.59ml/24h; P<0.001) in response to Angiotensin II, though WT and Het2k mice were not affected.

AngII infusion in Het1K, but not Het2k mice, led to significant exacerbation of hypertension and albuminuria. Our data suggests that the degree of nephron deficit is an important determinant of the risks associated with a reduced nephron endowment.

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