IL6 suppression provides renal protection independent of blood pressure in a murine model of salt-sensitive hypertension

Impaired cytochrome P450 epoxygenase enzyme ( Cyp2c) regulation contributes to renal damage in angiotensin salt-sensitive hypertension ( ANG/ HS). We hypothesized that interleukin-6 null mice ( IL6 -/ -) would improve Cyp2c regulation and reduce renal damage in hypertensive mice fed a high salt diet. Systolic blood pressure increased to a greater extent in ANG/ HS hypertension as compared to angiotensin ( ANG) hypertension but blood pressure did not differ between WT and IL6 -/ - hypertensive groups. Albuminuria, a marker for renal injury, increased significantly in ANG/ HS hypertension in WT mice ( 5,113 +/- 1,050 mu g/ day) and was attenuated in the ANG/ HS IL6 -/ - group ( 1,306 +/- 385 mu g/ day). Renal Cyp2c protein expression significantly decreased with ANG/ HS hypertension in WT mice as compared to high salt alone. However, the ability to upregulate Cyp2c expression in response to a high salt diet was restored in the ANG/ HS IL6 deficient hypertensive mice. Renal expression of soluble epoxide hydrolase, which inactivates protective epoxygenase metabolites, was significantly reduced in ANG/ HS IL6 -/ - hypertensive mice compared to the ANG/ HS WT group. These data suggest that IL6, while having no effect on blood pressure, impairs regulation of epoxygenase producing Cyp2c, which could contribute to the development of renal injury in angiotensin salt- sensitive hypertension.