PMID- 30668407 OWN - NLM STAT- MEDLINE DCOM- 20190715 LR - 20200310 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 53 DP - 2019 Feb TI - Anti-renal fibrosis effect of asperulosidic acid via TGF-beta1/smad2/smad3 and NF-kappaB signaling pathways in a rat model of unilateral ureteral obstruction. PG - 274-285 LID - S0944-7113(18)30291-5 [pii] LID - 10.1016/j.phymed.2018.09.009 [doi] AB - BACKGROUND: Renal fibrosis is the most common pathway leading to end-stage renal disease. It is characterized by excess extracellular matrix (ECM) accumulation and renal tissue damage, subsequently leading to kidney failure. Asperulosidic acid (ASPA), a bioactive iridoid glycoside, exerts anti-tumor, anti-oxidant, and anti-inflammatory activities, but its effects on renal fibrosis induced by unilateral ureteral obstruction (UUO) have not yet been investigated. PURPOSE: This study aimed to investigate the protective effect of ASPA on renal fibrosis induced by UUO, and to explore its pharmacological mechanism. METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: sham group, UUO model group, three ASPA treatment groups (10, 20, and 40 mg/kg), and captopril group (20 mg/kg). Rats were administered vehicle, ASPA or captopril intraperitoneally once a day for 14 consecutive days. Urea nitrogen (BUN), uric acid (UA) and inflammatory factors in serum samples were evaluated on the 7th, 10th, and 14th day after renal fibrosis induction. In addition, the 12 h urine was collected to test the content of urinary protein (upro) on the 14th day. The obstructive renal tissues were collected for pathological analysis (hematoxylin and eosion (H&E) staining and Masson's Trichrome staining) and immunohistochemical analysis on the 14th day after renal fibrosis induction. The mRNA expression of related factors and the protein levels of smad2, smad3, and smad4 were measured in UUO-induced rats by real time PCR and Western blot, respectively. RESULTS: The levels of BUN, UA, and upro were elevated in UUO-induced rats, but ASPA treatment improved renal function by reducing the levels of BUN, UA, and upro. The protein levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6, as well as the mRNA levels of TNF-alpha, IL-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1) and interferon-gamma (IFN-gamma), were decreased after ASPA administration (10, 20 and 40 mg/kg) in a dose-dependent manner. The ASPA exerted an alleviation effect on the inflammatory response through inhibition of nuclear factor-kappa B (NF-kappaB) pathway. In addition, reductions in alpha-smooth muscle actin (alpha-SMA), collagen III, and fibronectin expression were observed after ASPA administration at doses of 20 and 40 mg/kg. Furthermore, the renal expression of transforming growth factor-beta1 (TGF-beta1), smad2, smad3, and smad4 was down-regulated by ASPA treatment at doses of 20 and 40 mg/kg. CONCLUSION: ASPA possessed protective effects on renal interstitial fibrosis in UUO-induced rats. These effects may be through inhibition of the activation of NF-kappaB and TGF-beta1/smad2/smad3 signaling pathways. CI - Copyright (c) 2018 Elsevier GmbH. All rights reserved. FAU - Xianyuan, Lu AU - Xianyuan L AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. FAU - Wei, Zou AU - Wei Z AD - Key Laboratory of Hunan Province for Traditional Chinese Medicine in Obstetrics & Gynecology Research, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, Hunan, China. Electronic address: zouwei3@mail2.sysu.edu.cn. FAU - Yaqian, Dong AU - Yaqian D AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. FAU - Dan, Zhou AU - Dan Z AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. FAU - Xueli, Tong AU - Xueli T AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. FAU - Zhanglu, Dong AU - Zhanglu D AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. FAU - Guanyi, Liang AU - Guanyi L AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. FAU - Lan, Tang AU - Lan T AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. FAU - Menghua, Liu AU - Menghua L AD - Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China. Electronic address: liumenghua@smu.edu.cn. LA - eng PT - Journal Article DEP - 20180905 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Cytokines) RN - 0 (Glycosides) RN - 0 (NF-kappa B) RN - 0 (Protective Agents) RN - 0 (Smad2 Protein) RN - 0 (Smad2 protein, rat) RN - 0 (Smad3 Protein) RN - 0 (Smad3 protein, rat) RN - 0 (Transforming Growth Factor beta1) RN - 0 (asperulosidic acid) SB - IM MH - Animals MH - Cytokines/genetics/metabolism MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Fibrosis/*drug therapy/metabolism/pathology MH - Glycosides/administration & dosage/*pharmacology MH - Kidney/*drug effects/*metabolism/pathology MH - Kidney Diseases/drug therapy MH - Male MH - NF-kappa B/metabolism MH - Protective Agents/pharmacology MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects MH - Smad2 Protein/metabolism MH - Smad3 Protein/metabolism MH - Transforming Growth Factor beta1/metabolism MH - Ureteral Obstruction/*drug therapy/metabolism OTO - NOTNLM OT - Asperulosidic acid OT - NF-kappaB signaling pathway OT - Renal interstitial fibrosis OT - TGF-beta1/smad2/smad3 pathway OT - Unilateral ureteral obstruction (UUO) EDAT- 2019/01/23 06:00 MHDA- 2019/07/16 06:00 CRDT- 2019/01/23 06:00 PHST- 2018/04/21 00:00 [received] PHST- 2018/07/06 00:00 [revised] PHST- 2018/09/03 00:00 [accepted] PHST- 2019/01/23 06:00 [pubmed] PHST- 2019/07/16 06:00 [medline] PHST- 2019/01/23 06:00 [entrez] AID - S0944-7113(18)30291-5 [pii] AID - 10.1016/j.phymed.2018.09.009 [doi] PST - ppublish SO - Phytomedicine. 2019 Feb;53:274-285. doi: 10.1016/j.phymed.2018.09.009. Epub 2018 Sep 5.