Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension.
Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha and the profibrotic cytokine transforming growth factor-beta. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.
Crowley
Steven D
SD
Division of Nephrology, Department of Medicine, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, NC, USA. crow1004@mc.duke.edu
Frey
Campbell W
CW
Gould
Samantha K
SK
Griffiths
Robert
R
Ruiz
Phillip
P
Burchette
James L
JL
Howell
David N
DN
Makhanova
Natalia
N
Yan
Ming
M
Kim
Hyung-Suk
HS
Tharaux
Pierre-Louis
PL
Coffman
Thomas M
TM
D000419:Albuminuria / Q000188:drug therapy / Q000517:prevention & control; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D004195:Disease Models, Animal; D006973:Hypertension / Q000150:complications*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000009:adverse effects / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D017673:Sodium Chloride, Dietary; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D007371:Interferon-gamma; D009173:Mycophenolic Acid