Abstract
BackgroundRecently, we reported that toll-like receptor (TLR)2 and TLR4 localized on the glomerular endothelium in the glomeruli of streptozotocin (STZ)-induced type 1 diabetic mice and high fat diet feed-induced type 2 diabetic mice, and that periodontal pathogen Porphyromonas gingivalis LPS (Pg-LPS) administration lowered the survival rate of diabetic mice. The present study aims to examine the effect of TLR4 blocking on the suppression of Pg-LPS-induced diabetic nephropathy.MethodsThe survival rate and morphological/biochemical features for streptozotocin-induced diabetic mice with Pg-LPS and TLR4 blocker eritoran administration were investigated by reporter gene assay, urine and blood analysis, immunohistochemistry, and real time-PCR.Results and ConclusionsAll of the diabetic mice administered Pg-LPS were euthanized within the survival period of almost all of the diabetic mice. The blood urea nitrogen and creatinine, expression of TLR2 and TGF-b, and type 1 collagen accumulation, in the diabetic mice increased significantly with the Pg-LPS administration. In spite of the limited TLR4 activation with Pg-LPS, the TLR4 blocker eritoran decreased blood urea nitrogen and creatinine, and raised the survival rate of the Pg-LPS-administered diabetic mice slightly. The high expression levels of TLR2, TGF-b, and type 1 collagen in Pg-LPS-administered diabetic mice decreased with eritoran. Nuclear STAT3 which enhances TLR2 expression was detected in the TLR2-expressing glomeruli of diabetic mice. The TLR2 and STAT3 gene expression increased by the Pg-LPS administration but decreased with eritoran. These may suggest that Pg-LPS-induced diabetic nephropathy is mainly dependent on TLR2 signaling on glomerular endothelial cells, and that TLR4 blocker eritoran may play a role to slow the progress of diabetic nephropathy.
Highlights
We reported that toll-like receptor (TLR)2 and TLR4 localized on the glomerular endothelium in the glomeruli of streptozotocin (STZ)-induced type 1 diabetic mice and high fat diet feed-induced type 2 diabetic mice, and that periodontal pathogen Porphyromonas gingivalis LPS (Pg-LPS) administration lowered the survival rate of diabetic mice
The renal metabolic recognition of advanced glycation end products (AGE) by the toll-like receptor (TLR) which is a sensor for pathogen-associated molecular patterns common to bacterial components has been suggested as one candidate for the occurrence of diabetic nephropathy because as at least TLR2 and TLR4 are clearly detected in blood when diabetic nephropathy is established, and the blood AGE elevates the TLR2 and TLR4 levels in monocytes and glomeruli in diabetic nephropathy [8,9,10,11,12,13]
The PgLPS from Invivogen, the Pg-LPS from Wako, the Pg-LPS from P. gingivalis cultured with hemin, and the LPS with tetra-acylated lipid A structures formed an extremely low activity group, and the Pam3CSK4 showed little activity
Summary
We reported that toll-like receptor (TLR) and TLR4 localized on the glomerular endothelium in the glomeruli of streptozotocin (STZ)-induced type 1 diabetic mice and high fat diet feed-induced type 2 diabetic mice, and that periodontal pathogen Porphyromonas gingivalis LPS (Pg-LPS) administration lowered the survival rate of diabetic mice. In that study of the effects of the periodontal pathogen P. gingivalis lipopolysaccharide (LPS) which is a ligand of TLR2 and TLR4 in diabetic nephropathy, all diabetic mice subjected to repeated LPS administrations were euthanized within the survival period of all of the diabetic mice not administered LPS and of the survival period of all of the non-diabetic LPS-administered mice. Blood TLR ligands from periodontal pathogens like P. gingivalis may accumulate in the glomeluri and induce chronic renal inflammation, tissue repair, and glomerulosclerosis [23,24,25,26,27,28,29]. The TLR blockages may prevent the progress of diabetic nephropathy since albuminuria and glomerular hypertrophy in the TLR4 KO-STZ mice is less pronounced than in the wild type-STZ mice [30,31,32,33,34,35]
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