title: The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy.
abstract: OBJECTIVE
  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&amp;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.
authors: Sichuan University, West China Hospital, Department of Nephrolog, Wuhou District, Chengdu, Sichuan, China.
authors: Ruichao
authors: R
authors: Yu
authors: Hong
authors: H
authors: Bo
authors: Vincenzo
authors: V
authors: Villani
authors: Philip J
authors: PJ
authors: Spencer
authors: Ping
authors: P
authors: Fu
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D020381:Interleukin-17; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D020123:Sirolimus