Key result
Patients with Bartter's and Gitelman's syndromes had higher total plasma antioxidant power compared to controls (3.27 vs 1.05 mmol/l, P=0.002) and reduced intracellular responses to Ang II.
Why the study?
Does acute Angiotensin II stimulation alter oxidative stress-related gene expression differently in patients with Bartter's and Gitelman's syndromes compared to healthy controls?
Case-Control (n=19)
Does acute Angiotensin II stimulation alter oxidative stress-related gene expression differently in patients with Bartter's and Gitelman's syndromes compared to healthy controls?
Absolute Event Rate: 3.27% vs 1.05%
p-value: p=0.002
Patients with Bartter's and Gitelman's syndromes exhibit blunted intracellular reactive oxygen species responses to Angiotensin II, which may contribute to their characteristic vascular hyporeactivity.
May explain vascular hyporeactivity via blunted Ang II responses; hypothesis-generating and requires prospective validation before clinical consideration.
BACKGROUND: Bartter's and Gitelman's syndromes (BS/GS) have a blunted Gq protein-mediated cell signalling despite high circulating angiotensin II (Ang II) levels. This is associated with reduced Galphaq gene expression, intracellular inositol trisphosphate and Ca(++) release, PKC activity and cell reactivity. Ang II is a powerful stimulator of vascular oxidases but BS/GS patients show reduced total volatile LDL oxidation products and reduced LDL susceptibility to oxidation suggesting low level of oxidative stress. Therefore, we evaluated oxidative stress-related proteins in plasma and monocytes of patients with BS/GS, at baseline and after Ang II stimulation. METHODS: In two BS and seven GS patients, biochemically and genetically characterized, and in 10 age- and sex-matched control subjects, we measured total plasma antioxidant power (AOP), plasma peroxynitrite level and gene expression of the NADH/NADPH oxidase subunit p22(phox), TGFbeta and haeme oxygenase-1 (HO-1) in circulating monocytes in basal condition and after stimulation with Ang II. Furthermore, we investigated the C(242)T polymorphism of p22(phox), whose topography in a potential haeme-binding site suggests a role in the regulation of oxidative stress. RESULTS: AOP was higher in BS/GS patients than in controls (3.27 +/- 0.95 mmol/l vs 1.05 +/- 0.16, P = 0.002), together with higher plasma renin activity and aldosterone level (9.88 +/- 4.64 vs 0.95 +/- 0.08 nmol Ang I/h/ml, P < 0.0001; and 0.73 +/- 0.13 vs 0.18 +/- 0.01 nmol/l, P < 0.0001, respectively). The plasma peroxynitrite level was undetectable both in patients and controls. mRNA expression of p22(phox) and TGFbeta was reduced in BS/GS patients compared to controls [0.35 +/- 0.08 vs 0.53+/-0.05 densitometric units (d.u.), P = 0.005, and 0.82 +/- 0.07 vs 1.15 +/- 0.25 d.u., P = 0.006, respectively]. HO-1 mRNA was increased in BS/GS patients in comparison to controls (0.88 +/- 0.07 vs 0.78 +/- 0.11 d.u., P = 0.037). After acute Ang II exposure, p22(phox), TGFbeta and HO-1 gene expression significantly increased only in controls (from 0.59 +/- 0.12 to 0.96 +/- 0.11, P < 0.001, from 0.97 +/- 0.1 to 1.27 +/- 0.22, P < 0.008, and from 0.62 +/- 0.1 to 0.82 +/- 0.09, P < 0.001, respectively). Finally, C(242)T polymorphism of p22(phox) was undetectable. CONCLUSIONS: The intracellular responses to Ang II mediated by reactive oxygen species are reduced in BS/GS patients. This may contribute to their vascular hyporeactivity.
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Lorenzo Arcangelo Calò (2003) conducted a case-control in Bartter's and Gitelman's syndromes (n=19). Bartter's and Gitelman's syndromes vs. Age- and sex-matched controls was evaluated on Total plasma antioxidant power (AOP) (p=0.002). Patients with Bartter's and Gitelman's syndromes had higher total plasma antioxidant power compared to controls (3.27 vs 1.05 mmol/l, P=0.002) and reduced intracellular responses to Ang II.
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