Abstract
BackgroundThe overexpression of sodium-glucose cotransporter 2 (SGLT2) in diabetic kidneys has been reported. It has also been established that the diabetic glomerular endothelium expresses the toll-like receptors TLR2 and TLR4. The present study aims to examine the renal SGLT2 induction by the TLR2/4 ligand Porphyromonas (P.) gingivalis lipopolysaccharide (Pg-LPS) in mouse diabetic nephropathy.MethodsImmunohistochemical study and tissue RT-PCR analyses were performed on mouse kidneys in streptozotocin (STZ)-induced diabetic ICR mice (STZ-ICR), in healthy ICR mice administered Pg-LPS (LPS-ICR), and in diabetic ICR mouse kidneys with Pg-LPS-induced nephropathy (LPS-STZ).ResultsIn the quantitative analysis of blood sugar levels, the mean time to reach 600 mg/dl was shorter in the LPS-STZ than in the STZ-ICR kidneys. The rise in blood glucose levels was significantly steeper in the LPS-STZ than in the STZ-ICR kidneys. According to these data the LPS-STZ model suggests a marked glucose intolerance. The expression of SGLT2 was significantly stronger in the whole of the renal parenchyma of the LPS-STZ than in the LPS-ICR or in the STZ-ICR. The expression of SGLT2 was observed both in the renal tubules and around the renal tubules, and in the glomeruli of the LPS-STZ kidneys. In the analysis by tissue real-time PCR and cell ELISA, the expression of the SGLT2 gene and protein was significantly stronger in the LPS-STZ than in the LPS-ICR or in the STZ-ICR. There were no differences in the renal SGLT2 production in the LPS-ICR and the STZ-ICR kidneys.ConclusionsAbnormally high renal expression of SGLT2 occurs in diabetic kidneys with P. gingivalis LPS. Periodontitis may be an exacerbating factor in diabetic nephropathy as well as in diabetes.
Highlights
The overexpression of sodium-glucose cotransporter 2 (SGLT2) in diabetic kidneys has been reported
There were no significant differences in the renal gene expression of SGLT2 between P. gingivalis lipopolysaccharide-administered ICR mice (LPS-ICR) and Streptozotocininduced diabetic ICR mice (STZ-ICR)
Reaction products of antiSGLT2 were detected in only the renal proximal tubules of STZ-ICR whereas the reaction products were detected both in the renal tubules as well as at the outer wall of LPS-STZ (Fig. 4)
Summary
The overexpression of sodium-glucose cotransporter 2 (SGLT2) in diabetic kidneys has been reported. The present study aims to examine the renal SGLT2 induction by the TLR2/4 ligand Porphyromonas (P.) gingivalis lipopolysaccharide (Pg-LPS) in mouse diabetic nephropathy. The TLR recognizes pathogen-associated molecular patterns like lipopolysaccharide (LPS) in microorganism components, and elevated levels of TLR2/4 expression have been reported in leukocytes in diabetic patients [8,9,10,11,12]. The periodontal pathogen Porphyromonas (P.) gingivalis LPS (Pg-LPS) induces the production of inflammatory agents by host defense systems recognizing lipid A and coexisting molecules of TLR2 and TLR4 [18,19,20]. It is thought that patients with severe periodontitis are liable to cause bacteremia of the systemic circulation with oral microorganisms, resulting in the renal accumulation of bacterial components or the immune complexes like in IgA nephropathy [23,24,25]. Intestinal microorganisms enter the circulation but are directly sterilized in the liver while oral microorganisms enter the systemic circulation directly; this has led to the suggestion that head and neck infections spread throughout the body and enter the kidney via the systemic circulation [24,25,26,27]
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