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

Abstract

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 extracellularmatrix-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.

Biochemical Studies of Hippocampal Gene Expression of Brain-Derived Neurotropic Factor and Toll-Like Receptor-4 in Diabetic Rats Exposed to Chronic Stress: Effects of Antidepressant Drugs

“…In this context, monocytes isolated from diabetic patients showed increased TLR-4 expression and TLR-mediated inflammation, this was significantly correlated with HbA1c levels [32]. TLR-4 expression was increased in diabetic nephropathy patients [33]. Levels of TNF-α were significantly elevated in the blood of patients with type 2 DM in association with increased blood sugar indices and insulin resistance [34].…”

Treatment and impact of dyslipidemia in diabetic nephropathy

“…In addition to this study, a lot of basic research has discovered the mechanisms between dyslipidemia and diabetic nephropathy [14]. Studies revealed that transforming growth factor-b signaling [15], renin-angiotensin system [16], S100A8/TLR4 signaling [17], and oxidative stress [18] may play an important role in the progression of diabetic nephropathies. Concerning the development of albuminuria, the importance of the deterioration of glycocalyx, which is on the surface of endothelium, was highlighted [19].…”

26 Intestinal Dysbiosis Contributes to the Delayed Gastrointestinal Transit in High Fat Diet Fed Mice

“…26 Moreover, saturated fatty acids such as palmitate, a major fatty acid in HFD, can activate TLR4 signaling, 27,28 and hyperlipidemia leads to TLR4-dependent renal damages. 29 The effects of HFD and LPS together on the enteric nervous system is not known. Because a HFD increases circulating LPS and can impact TLR4 signaling in the gut we hypothesized that the enteric neuronal alteration induced by the HFD feeding is dependent on TLR4 activation.…”