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 mug/day) and was attenuated in the ANG/HS IL6-/- group (1,306 +/- 385 mug/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.
Manhiani
M M
MM
Department of Vascular Biology, Medical College of Georgia, Augusta, GA, USA.
Quigley
J E
JE
Socha
M J
MJ
Motamed
K
K
Imig
J D
JD
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control; D015850:Interleukin-6 / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage* / Q000009:adverse effects; D000093242:Interleukin-6 Inhibitors
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D015850:Interleukin-6; D017673:Sodium Chloride, Dietary; D000093242:Interleukin-6 Inhibitors; C400322:cytochrome P-450 CYP2C subfamily