CTGF promotes inflammatory cell infiltration of the renal interstitium by activating NF-kappaB.
Connective tissue growth factor (CTGF) is an important profibrotic factor in kidney diseases. Blockade of endogenous CTGF ameliorates experimental renal damage and inhibits synthesis of extracellular matrix in cultured renal cells. CTGF regulates several cellular responses, including adhesion, migration, proliferation, and synthesis of proinflammatory factors. Here, we investigated whether CTGF participates in the inflammatory process in the kidney by evaluating the nuclear factor-kappa B (NF-kappaB) pathway, a key signaling system that controls inflammation and immune responses. Systemic administration of CTGF to mice for 24 h induced marked infiltration of inflammatory cells in the renal interstitium (T lymphocytes and monocytes/macrophages) and led to elevated renal NF-kappaB activity. Administration of CTGF increased renal expression of chemokines (MCP-1 and RANTES) and cytokines (INF-gamma, IL-6, and IL-4) that recruit immune cells and promote inflammation. Treatment with a NF-kappaB inhibitor, parthenolide, inhibited CTGF-induced renal inflammatory responses, including the up-regulation of chemokines and cytokines. In cultured murine tubuloepithelial cells, CTGF rapidly activated the NF-kappaB pathway and the cascade of mitogen-activated protein kinases, demonstrating crosstalk between these signaling pathways. CTGF, via mitogen-activated protein kinase and NF-kappaB activation, increased proinflammatory gene expression. These data show that in addition to its profibrotic properties, CTGF contributes to the recruitment of inflammatory cells in the kidney by activating the NF-kappaB pathway.
Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma Madrid, Madrid, Spain.
Elsa
E
Sánchez-López
Sandra
S
Rayego
Raquel
R
Rodrigues-Díez
Javier Sánchez
JS
Rodriguez
Raúl
R
Rodrigues-Díez
Juan
J
Rodríguez-Vita
Gisselle
G
Carvajal
Luiz Stark
LS
Aroeira
Rafael
R
Selgas
Sergio A
SA
Mezzano
Alberto
A
Ortiz
Jesús
J
Egido
Marta
M
Ruiz-Ortega
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C526318:CCN2 protein, mouse; D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; D012717:Sesquiterpenes; D055513:Connective Tissue Growth Factor; C002669:parthenolide; D020929:Mitogen-Activated Protein Kinase Kinases