Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney.
BACKGROUND
Emerging evidence suggests that angiotensin II (Ang II) is not only a vasoactive peptide, but also a true cytokine that regulates cell growth, inflammation and fibrosis. Many studies have demonstrated that this peptide plays an active role in the progression of renal injury. Some of Ang II-induced effects are mediated by the production of a large array of growth factors. The aim of this study was to investigate whether Ang II could regulate the expression of cytokines and chemokines in the kidney and its correlation with the Ang II-induced renal damage.


METHODS
The model of Ang II-induced renal damage was done by systemic Ang II infusion into normal rats (50 ng/kg/min; subcutaneous osmotic minipumps). In addition, the implication of Ang II was investigated in a model of immune complex nephritis in rats treated with the angiotensin converting enzyme (ACE) inhibitor quinapril. The mRNA expression was analyzed by RT-PCR and/or Northern blot, and protein levels by Western blot and/or immunohistochemistry.


RESULTS
Rats infused with Ang II for 3 days caused elevated renal expression of tumor necrosis factor-alpha (TNF-alpha; gene and protein levels). TNF-alpha positive cells were observed in glomeruli (mainly in endothelial cells), tubules and vessels. In rats with immune complex nephritis, the renal overexpression of TNF-alpha was diminished by the ACE inhibitor quinapril. Systemic infusion of Ang II also increased renal synthesis of cytokines (interleukin-6, IL-6) and chemokines (monocyte chemoattractant protein-1; MCP-1) that were associated with elevated tissue levels of activated nuclear factor-kappaB (NF-kappaB) and the presence of inflammatory cell infiltration.


CONCLUSIONS
Ang II in vivo increases TNF-alpha production in the kidney. Ang II also up-regulates other proinflammatory mediators, including IL-6, MCP-1 and NF-kappaB, coincidentally associated to the presence of glomerular and interstitial inflammatory cells in the kidney. All these data further strengthen the idea that Ang II plays an active role in the inflammatory response in renal diseases.
Ruiz-Ortega
Marta
M
Laboratory of Vascular and Renal Pathology, Fundación Jiménez Díaz, Universidad Autónoma, Hospital Clínico, Madrid, Spain. mruizo@fjd.es
Ruperez
Mónica
M
Lorenzo
Oscar
O
Esteban
Vanesa
V
Blanco
Julia
J
Mezzano
Sergio
S
Egido
Jesus
J
D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007105:Immune Complex Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D007260:Infusion Pumps; D007263:Infusions, Parenteral; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism; D009393:Nephritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D000077583:Quinapril; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D000806:Angiotensin-Converting Enzyme Inhibitors; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D000077583:Quinapril