Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

• Published in: Diabetologia Vol. 55; no. 8; pp. 2256 - 2266
• Main Authors: Kuwabara, T., Mori, K., Mukoyama, M., Kasahara, M., Yokoi, H., Saito, Y., Ogawa, Y., Imamaki, H., Kawanishi, T., Ishii, A., Koga, K., Mori, K. P., Kato, Y., Sugawara, A., Nakao, K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2012; Springer; Springer Nature B.V
• Subjects: Animal models; Animals; Associated diseases and complications; Biological and medical sciences; Biopsy; Calcium-binding protein; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - pathology; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - blood; Diabetic Nephropathies - etiology; Diabetic Nephropathies - pathology; Diabetic nephropathy; Diet; Disease Progression; Disorders of blood lipids. Hyperlipoproteinemia; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Gene expression; High fat diet; Human Physiology; Humans; Hyperlipidemia; Hyperlipidemias - blood; Hyperlipidemias - complications; Hyperlipidemias - pathology; Hypertension; Inflammation; Injuries; Interferon; Interferon regulatory factor 3; Internal Medicine; Kidney; Kidney - pathology; Kidneys; Ligands; Macrophages; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Nephrology. Urinary tract diseases; Nephropathy; Phosphorylation; Proteins; Real-Time Polymerase Chain Reaction; Risk factors; S100A8 protein; Signal Transduction; Streptozocin; Streptozocin - pharmacology; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; University graduates; Urinary system involvement in other diseases. Miscellaneous; United States > US; Japan; High-fat diet; Glomerulus; Diabetic nephropathy; Hyperlipidaemia; Macrophages; TLR4; S100A8; Endocrinopathy; Lipids; Toll like receptor; Hyperlipemia; Dyslipemia; Kidney disease; Urinary system disease; Diabetes mellitus; Rodentia; Metabolic diseases; Feeding; Concomitant disease; Vertebrata; Mammalia; Diet; Mouse; Animal; Macrophage
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-012-2578-1

Aims/hypothesis Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. Methods Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. Results Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellular-matrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. Conclusions/interpretation Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.