Abstract 294: Evaluation of the Role of the NAD(P)H Oxidase Subunit p67phox in the Regulation of Glomerular Filtration Rate in Dahl Salt-sensitive Rats

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Studies were performed in male Dahl salt-sensitive (SS) rats with a null mutation in the p67phox gene (SSp67phox -/-) and wild type littermates (SS-WT) aged 10-12 weeks (n=5/6 /group). In previous studies we have shown that this important subunit of NADPH oxidase is upregulated in the SS rat. A new method for sequential measurement of GFR in conscious rats was applied during the consumption of a high salt diet. Utilizing a miniaturized device, disappearance curves of fluorescein isothiocynate (FITC)-sinistrin were determined by transcutaneous excitation and real time detection of the emitted light through the skin. The rats were surgically prepared with femoral venous catheters for the administration of (FITC)-sinistrin and carotid catheters for MAP measurement by telemetry. Baseline measurement of GFR and MAP were made daily to obtain 2 stable control days on low salt (LS, 0.4% NaCl). High salt (HS, 4.0% NaCl) measurements were made on day 2,5,7,14 and 21. In SS-WT rats, HS resulted in a progressive and significant increase in MAP (from 126±2 mmHg during LS to 158±11 mmHg by d21 HS). GFR decreased significantly from 1.50±0.03 ml/min/100g bwgt during LS to 1.26±0.02 by d21 HS. Notably, a significant increase in blood pressure was observed at d7 HS in the SS-WT preceeding the reduction in GFR which did not occur until d14 HS. In rats with the null mutation of the p67phox gene, the pressor response to HS was blunted, MAP averaged 131±5 mmHg by d21, and there was no significant change in GFR (LS values 1.54±0.07 ml/min/100g bwgt comparable to d21 HS values of 1.41±0.04). In summary, when p67phox is not functional in the SS rat, the hypertensive response to HS is blunted and GFR is maintained. We conclude that reactive oxygen species production via NADPH oxidase plays a major role in the eventual reduction of GFR in SS rats following the development of hypertension.

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