The Rho-kinase pathway regulates angiotensin II-induced renal damage.
BACKGROUND
Angiotensin II (AngII) is a key factor in the pathogenesis of renal damage. AngII via AngII type 1 receptors activates several intracellular signaling systems, including the small guanosine triphosphatase Rho and its downstream effector Rho-dependent serine-threonine kinase (Rho-kinase). The Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes observed in cardiovascular diseases. However, the data on renal diseases are scarce. The aim of this study was to investigate the effect of Rho-kinase inhibition in AngII-induced renal damage.


METHODS
We used the model of systemic AngII infusion into normal rats (100 ng/kg per minute; subcutaneous osmotic minipumps), and some animals were treated with the Rho-kinase inhibitor Y-27632 (30 mg/kg per day). In the kidneys of these animals, we evaluated renal lesions, transcription factor activity (by electrophoretic mobility shift assay), and messenger RNA (by polymerase chain reaction) and protein expression levels (by Western blot and/or immunohistochemistry) of proinflammatory and profibrotic factors.


RESULTS
Rats infused with AngII for three days present renal inflammatory cell infiltration and slight tubular damage, which were diminished by treatment with the Rho-kinase inhibitor Y-27632. AngII activates nuclear factor-kappaB and causes overexpression of proinflammatory factors, including cytokines (tumor necrosis factor alpha) and chemokines (monocyte chemotactic protein-1), and of profibrotic factors (connective tissue growth factor). Treatment of AngII-infused rats with Y-27632 decreases the upregulation of these proinflammatory and profibrotic mediators.


CONCLUSIONS
These data demonstrate that the Rho-kinase pathway is involved in renal damage caused by AngII through the regulation of proinflammatory and profibrotic mediators. These results suggest that inhibition of the Rho-kinase pathway represents a novel therapy for renal diseases associated with local AngII generation.
Rupérez
Mónica
M
Vascular and Renal Research Laboratory, Fundación Jiménez Diaz, Universidad Autónoma, Madrid, Spain.
Sánchez-López
Elsa
E
Blanco-Colio
Luis Miguel
LM
Esteban
Vanesa
V
Rodríguez-Vita
Juan
J
Plaza
Juan José
JJ
Egido
Jesús
J
Ruiz-Ortega
Marta
M
D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D055513:Connective Tissue Growth Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000209:etiology* / Q000503:physiopathology*; D016328:NF-kappa B / Q000502:physiology; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012234:Rho Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases
D000577:Amides; C526316:CCN2 protein, rat; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D012234:Rho Factor; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C108830:Y 27632; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases