Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus.
Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-α blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68(+) cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor κB (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor κB, oxidative stress, and inflammation.
Venegas-Pont
Marcia
M
Department of Physiology and Biophysics, Center for Excellence in Cardiovascular Renal Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505, USA.
Manigrasso
Michaele B
MB
Grifoni
Samira C
SC
LaMarca
Babbette B
BB
Maric
Christine
C
Racusen
Lorraine C
LC
Glover
Porter H
PH
Jones
Allison V
AV
Drummond
Heather A
HA
Ryan
Michael J
MJ
D000419:Albuminuria / Q000517:prevention & control / Q000652:urine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000652:urine; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000652:urine; D000068800:Etanercept; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000517:prevention & control; D006973:Hypertension / Q000503:physiopathology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000503:physiopathology* / Q000652:urine; D051379:Mice; D008815:Mice, Inbred Strains; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097382:CD68 Molecule
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D003404:Creatinine; D019332:Endothelin-1; D000068800:Etanercept; D007074:Immunoglobulin G; D019255:NADPH Oxidases; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C491768:Ccl2 protein, mouse