PMID- 26849067
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20161230
IS  - 1423-0143 (Electronic)
IS  - 1420-4096 (Linking)
VI  - 41
IP  - 1
DP  - 2016
TI  - The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in 
      the Early Stage of Rat Diabetic Nephropathy.
PG  - 55-69
LID - 10.1159/000368547 [doi]
AB  - 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.
CI  - (c) 2016 The Author(s) Published by S. Karger AG, Basel.
FAU - Yu, Ruichao
AU  - Yu R
AD  - Sichuan University, West China Hospital, Department of Nephrolog, Wuhou District, 
      Chengdu, Sichuan, China.
FAU - Bo, Hong
AU  - Bo H
FAU - Villani, Vincenzo
AU  - Villani V
FAU - Spencer, Philip J
AU  - Spencer PJ
FAU - Fu, Ping
AU  - Fu P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160207
PL  - Switzerland
TA  - Kidney Blood Press Res
JT  - Kidney & blood pressure research
JID - 9610505
RN  - 0 (Interleukin-17)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Experimental/*drug therapy/metabolism/pathology
MH  - Diabetic Nephropathies/*drug therapy/metabolism/pathology
MH  - Disease Progression
MH  - Interleukin-17/*antagonists & inhibitors/biosynthesis
MH  - Male
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sirolimus/*therapeutic use
MH  - Toll-Like Receptor 4/*antagonists & inhibitors/biosynthesis
EDAT- 2016/02/06 06:00
MHDA- 2016/12/15 06:00
CRDT- 2016/02/06 06:00
PHST- 2015/12/08 00:00 [accepted]
PHST- 2016/02/06 06:00 [entrez]
PHST- 2016/02/06 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - 000368547 [pii]
AID - 10.1159/000368547 [doi]
PST - ppublish
SO  - Kidney Blood Press Res. 2016;41(1):55-69. doi: 10.1159/000368547. Epub 2016 Feb 
      7.