High-mobility group box-1 protein promotes granulomatous nephritis in adenine-induced nephropathy.
Granulomatous nephritis can be triggered by diverse factors and results in kidney failure. However, despite accumulating data about granulomatous inflammation, pathogenetic mechanisms in nephritis remain unclear. The DNA-binding high-mobility group box-1 protein (HMGB1) initiates and propagates inflammation when released by activated macrophages, and functions as an 'alarm cytokine' signaling tissue damage. In this study, we showed elevated HMGB1 expression in renal granulomas in rats with crystal-induced granulomatous nephritis caused by feeding an adenine-rich diet. HMGB1 levels were also raised in urine and serum, as well as in monocyte chemoattractant protein-1 (MCP-1), a mediator of granulomatous inflammation. Injection of HMGB1 worsened renal function and upregulated MCP-1 in rats with crystal-induced granulomatous nephritis. HMGB1 also induced MCP-1 secretion through mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) pathways in rat renal tubular epithelial cells in vitro. Hmgb1(+/-) mice with crystal-induced nephritis displayed reduced MCP-1 expression in the kidneys and in urine and the number of macrophages in the kidneys was significantly decreased. We conclude that HMGB1 is a new mediator involved in crystal-induced nephritis that amplifies granulomatous inflammation in a cycle where MCP-1 attracts activated macrophages, resulting in excessive and sustained HMGB1 release. HMGB1 could be a novel target for inhibiting chronic granulomatous diseases.
Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Yoko
Y
Oyama
Teruto
T
Hashiguchi
Noboru
N
Taniguchi
Salunya
S
Tancharoen
Tomonori
T
Uchimura
Kamal K
KK
Biswas
Ko-Ichi
K
Kawahara
Takao
T
Nitanda
Yoshihisa
Y
Umekita
Martin
M
Lotz
Ikuro
I
Maruyama
D000225:Adenine / Q000494:pharmacology*; D000818:Animals; D001806:Blood Urea Nitrogen; D018932:Chemokine CCL2 / Q000187:drug effects / Q000235:genetics; D003404:Creatinine / Q000097:blood; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006099:Granuloma / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D024243:HMGB1 Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology / Q000502:physiology; D051379:Mice; D009393:Nephritis / Q000139:chemically induced* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D024243:HMGB1 Protein; D003404:Creatinine; D019869:Phosphatidylinositol 3-Kinases; D000225:Adenine