PMID- 25547416
OWN - NLM
STAT- MEDLINE
DCOM- 20150910
LR  - 20211203
IS  - 1421-9778 (Electronic)
IS  - 1015-8987 (Linking)
VI  - 35
IP  - 1
DP  - 2015
TI  - Rapamycin attenuates aldosterone-induced tubulointerstitial inflammation and 
      fibrosis.
PG  - 116-25
LID - 10.1159/000369680 [doi]
AB  - BACKGROUND/AIM: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated 
      in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was 
      to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced 
      tubulointerstitial inflammation and fibrosis. METHODS: Uninephrectomized, 
      Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to 
      receive treatment for 28 days as follows: vehicle infusion (control), 0.75 mug/h 
      Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by 
      intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal 
      inflammation was investigated using Masson's technique, immunohistochemistry, and 
      western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal 
      transition (EMT) process and on TNF-alpha mRNA expression and secretion in cultured 
      HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR 
      and ELISA. RESULTS: An in vivo study indicated that signaling by the mammalian 
      target of Rap (mTOR) was activated in rats in the Aldo group compared to 
      controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In 
      addition, the inflammatory response increased, as evidenced by increases in 
      inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of 
      extracellular matrix (ECM), as indicated by increased collagen I and fibronectin 
      expression and pro-fibrogenic gene (PAI-1 and TGF-beta1) expression. These changes 
      were attenuated by Rap treatment. An in vitro study showed that Rap significantly 
      suppressed the Aldo-induced EMT process and TNF-alpha mRNA expression and secretion 
      in cultured HK-2 cells. CONCLUSIONS: Rap can ameliorate tubulointerstitial 
      inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a 
      major cell type involved in this physiologic process.
CI  - (c) 2015 S. Karger AG, Basel.
FAU - Wang, Bin
AU  - Wang B
AD  - Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan 
      University, Shanghai, China.
FAU - Ding, Wei
AU  - Ding W
FAU - Zhang, Minmin
AU  - Zhang M
FAU - Li, Hongmei
AU  - Li H
FAU - Gu, Yong
AU  - Gu Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150102
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 4964P6T9RB (Aldosterone)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Aldosterone/toxicity
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology/therapeutic use
MH  - Cell Line
MH  - Epithelial-Mesenchymal Transition/*drug effects
MH  - Extracellular Matrix/metabolism
MH  - Fibrosis/chemically induced/drug therapy/*pathology
MH  - Humans
MH  - Male
MH  - Nephritis, Interstitial/chemically induced/drug therapy/*pathology
MH  - Phosphorylation/drug effects
MH  - Plasminogen Activator Inhibitor 1/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Transforming Growth Factor beta1/metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/metabolism
MH  - Up-Regulation/drug effects
EDAT- 2014/12/31 06:00
MHDA- 2015/09/12 06:00
CRDT- 2014/12/31 06:00
PHST- 2014/11/10 00:00 [accepted]
PHST- 2014/12/31 06:00 [entrez]
PHST- 2014/12/31 06:00 [pubmed]
PHST- 2015/09/12 06:00 [medline]
AID - 000369680 [pii]
AID - 10.1159/000369680 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2015;35(1):116-25. doi: 10.1159/000369680. Epub 2015 Jan 2.