The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy

Abstract

Background/Aims: There is increasing evidence showing that innate immune responses and inflammatory processes play an important role in the development and progression of diabetic nephropathy (DN). The potential effect of innate immunity in the early stage of DN is still unclear. Toll-Like-Receptor 4 (TLR4) is vigorously involved in the progress of kidney diseases in a sterile environment. The activation of the interleukin 17 (IL-17) pathway produces inflammatory cytokines, appearing in various kidney diseases. Unfortunately the relationship between TLR4 and IL-17 has not been investigated in diabetic nephropathy to date. The aim of this study is to investigate whether mammalian target of rapamycin (mTOR) inhibition may be dependent on TLR4 signaling and the pro-inflammatory factor IL-17 to delay the progression of DN. Methods: Streptozotocin (STZ)-induced diabetic rats were randomly assigned to 3 experimental groups: a diabetic nephropathy group (DN, n = 6); and a diabetic nephropathy treated with rapamycin group (Rapa, n = 6) and a control group (Control, n =6). Body weight, fasting blood sugar, and 24h urine albumin were assessed at week 2, week 4 and week 8. Renal tissues were harvested for H&E, PAS staining, as well as an immunohistochemistry assay for TLR4 and IL-17. TLR4 quantitative expression was measured by Western-Blot analysis and RT-PCR. Results: Our results demonstrated that the expression of both TLR4 and IL-17 were upregulated in early stage DN and reduced by rapamycin. TLR4 and IL-17 both increased and positively related to 24h urinary albumin and kidney/weight ratio. However, neither TLR4 nor IL-17 made a significant difference on fasting blood sugar. Conclusions: Taken together, our results confirm and extend previous studies identifying the significance of the TLR4 and Th17 pathways in development of early stage DN. Furthermore, we suggest this overexpression of TLR4 might be involved in the immunopathogenesis of DN through activation of Th17 cells. Rapamycin may attenuate DN via reduction of the TLR4 signaling pathway and Th17 cells signaling. Although the underlying mechanisms need to be explored, the observed increase of TLR4 and IL-17 during the early stages of DN and their suppression with rapamycin treatment suggest the importance of TLR4 and IL-17 in DN pathophysiology.

Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy

“…Toll-like receptor-4 (TLR-4) promotes tubule-interstitial inflammation in DN and is essential for IL-17A generation. 35,36 Blockade of IL-17A significantly diminished tlr-4 mRNA upregulation in diabetic kidneys (Figure 6c).…”

MiR‐874 alleviates renal injury and inflammatory response in diabetic nephropathy through targeting toll‐like receptor‐4

“…miR-874 can inhibit TNF-α-induced remodeling in human fetal airway smooth muscle cells via targeting STAT3 (Sun et al, 2018). In addition, miR-874 is significantly downregulated in HG-stimulated human aortic endothelial cells (HAEC) (Lo, Peng, & Wang, 2017 (Yu, Bo, Villani, Spencer, & Fu, 2016). Besides, TLR4 can link inflammation and fibrosis in chronic kidney diseases (Lepenies et al, 2011).…”

Interleukin 17A and Toll-like Receptor 4 in Patients with Arterial Hypertension

“…Notably, to date approximately a dozen TLRs have been identified only in mammals, and the most extensive research linking arterial hypertension and TLRs has been performed on TLR4 [15-18]. TLR4 is also thought to play an important role in acute renal failure and diabetic nephropathy [19, 20]. However, these studies have all utilized animal models or cell culture; and only a few clinical studies have investigated the correlation between TLR and human hypertension.…”