Abstract
Kidney damage is markedly accelerated by high-salt (HS) intake in stroke-prone spontaneously hypertensive rats (SHRSP). Epoxyeicosatrienoic acids (EETs) are epoxygenase products of arachidonic acid which possess vasodepressor, natriuretic, and anti-inflammatory activities. We examined whether up-regulation (clofibrate) or inhibition [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH)] of epoxygenase would alter systolic blood pressure (SBP) and/or renal pathology in SHRSP on HS intake (1% NaCl drinking solution). Three weeks of treatment with clofibrate induced renal cortical protein expression of CYP2C23 and increased urinary excretion of EETs compared with vehicle-treated SHRSP. SBP and urinary protein excretion (UPE) were significantly lowered with clofibrate treatment. Kidneys from vehicle-treated SHRSP, which were on HS intake for 3 weeks, demonstrated focal lesions of vascular fibrinoid degeneration, which were markedly attenuated with clofibrate treatment. In contrast, 2 weeks of treatment with the selective epoxygenase inhibitor, MS-PPOH, increased UPE without significantly altering neither urinary EET levels nor SBP. Kidneys from vehicle-treated SHRSP, which were on HS intake for 11 days, demonstrated occasional mild damage whereas kidneys from MS-PPOH-treated rats exhibited widespread malignant nephrosclerosis. These results suggest that pharmacological manipulation of epoxygenase results in divergent effects on renal damage and that interventions to increase EET levels may provide therapeutic strategies for treating salt-sensitive hypertension and renal damage.
Highlights
Salt-sensitivity is an important characteristic of a subgroup of humans with essential hypertension (Katori and Majima, 2008)
In vehicle-treated stroke-prone spontaneously hypertensive rat (SHRSP), systolic blood pressure (SBP) progressively increased from 176 ± 4 mmHg at 1 week to 197 ± 5 mmHg at 3 weeks of the study (P < 0.01)
SBP was significantly lower in clofibrate-treated SHRSP at each week of the study (149 ± 4 mmHg at 1 week, P < 0.01 vs. vehicle; 167 ± 8 mmHg at 3 weeks, P < 0.05 vs. vehicle)
Summary
Salt-sensitivity is an important characteristic of a subgroup of humans with essential hypertension (Katori and Majima, 2008). High dietary salt increases the susceptibility of hypertensive patients to renal damage (Cowley and Roman, 1996). The stroke-prone substrain (A3N) of the spontaneously hypertensive rat (SHR), or stroke-prone SHR (SHRSP), is a well-established model of genetic hypertension in which end-organ damage is highly salt-sensitive. Studies in experimental animal models provide substantial evidence for EETs in the regulation in inflammation, fibrosis, and platelet aggregation (Node et al, 1999; Krotz et al, 2004). These properties of EETs enable them to serve in a variety of settings to protect and sustain both renal and systemic circulatory function.
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