O23
Disruption of renal ADMA metabolism leads to salt-sensitive hypertension
Zhen Wang, Olga Boruc, Anna Slaviero, David C Wheeler, James Leiper and Ben Caplin
UCL Centre for Nephrology and MRC Clinical Sciences Centre, London
Background: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide
(NO) synthesis found at increased concentrations in patients with renal failure. High ADMA
levels have been implicated as one factor underlying the increased cardiovascular (CV) risk in
chronic kidney disease (CKD). Although increases in ADMA have been proposed to cause
endothelial dysfunction through reductions in vascular NO bioavailability, experimental studies
have failed to demonstrate this effect at the plasma concentrations of ADMA observed in CKD.
As NO also regulates tubular sodium handling, an alternative explanation for the detrimental
vascular effects ADMA is through a salt-dependent mechanism. We have recently demonstrated
that the predominantly renal tubular enzyme alanine-glyoxylate aminotransferase-2 (AGXT2)
plays an important role in regulating circulating ADMA levels. Therefore we examined the
detailed CV phenotype of AGXT2 knockout (KO) mice.
Methods: Serum urea, creatinine, ADMA and renin levels were measured and renal histology
examined in AGXT2 KO and wild-type (WT) littermates. Ex-vivo vascular responses to
endothelial-dependent agonists were also explored. Telemetry probes were implanted in
AGXT2 KO and WT animals under general anaesthetic at 12-14 weeks of age. Two weeks later,
continuous BP recordings were performed for 24-48 hours at baseline on a standard (0.3%
sodium) diet and then again following 2-weeks of a low-sodium (0.03%) diet. Telemetry data
were analysed using a multi-level model with BP readings nested within animals and the impact
of genotype, diet and genotype-diet interaction examined.
160
Standard Diet
Low-Salt Diet
155
Mean Systolic Blood Pressure (mmHg)
Results: Serum ADMA levels were
0.2μMol/L (95% CI: 0.05-0.35;
P<0.05) higher in AGXT2 KO vs
WT mice. AGXT2 KO animals had
morphologically normal kidneys
and no evidence of impaired renal
function although there was a trend
toward lower renin levels. There
was no evidence of impaired
endothelial-dependent dilatation in
arterial rings from AGXT2 KO
mice.
Mean systolic BP was
8.8mmHg
(0.6-17.0;
P<0.05)
higher in AGXT2 KO vs WT mice
at baseline. Overall systolic BP fell
by a mean of 2.1mmHg (1.8-2.5;
P<0.005) on a low-sodium diet but
there was an additional 7.3mmHg
(6.7-7.9; P<0.005) fall in the
AGXT2 KO mice (Figure).
150
WT
AGXT2 KO
145
140
135
130
125
120
115
110
Time (hours)
Figure: Mean Systolic BP in WT and AGXT2 KO mice from 24-hour telemetry
recordings at baseline (left) and afer 2-weeks on a low-salt diet (right). P<0.05
for a difference between genotypes at baseline, NS on low-salt diet.
Conclusions: Vessels from AGXT2 KO mice are functionally normal ex-vivo confirming this
enzyme does not mediate an effect by altering ADMA metabolism in the endothelium. The
hypertension due to disruption of AGXT2 is almost entirely abrogated by a low-sodium diet.
These findings raise the possibility that increased renal tubular sodium reabsorption underlies
ADMA-induced vascular dysfunction. Increasing renal tubular AGXT2 activity might represent
a novel therapeutic strategy in CKD-associated vascular disease.