Effect of BBT-877, a novel inhibitor of ATX, on a mouse model of type 1 diabetic nephropathy

被引:8
作者
Lee, Jong Han [1 ]
Khin, Phyu Phyu [2 ,3 ,7 ]
Lee, GwangHee [4 ,5 ]
Lim, Oh Kyung [6 ]
Jun, Hee-Sook [2 ,3 ,7 ]
机构
[1] Hanseo Univ, Dept Marine Bio & Med Sci, Seosan, South Korea
[2] Gachon Univ, Coll Pharm, Incheon, South Korea
[3] Gachon Univ, Gachon Inst Pharmaceut Sci, Incheon, South Korea
[4] Bridge Biotherapeut Inc, Seongnam, South Korea
[5] Boostimmune Therapeut Inc, Seongnam, South Korea
[6] Gachon Univ, Dept Rehabil Med, Incheon, South Korea
[7] Gachon Univ, Lee Gil Ya Canc & Diabet Inst, Incheon, South Korea
来源
AGING-US | 2022年 / 14卷 / 16期
基金
新加坡国家研究基金会;
关键词
streptozotocin-induced diabetic mice; BBT-877; autotaxin; diabetic nephropathy; LYSOPHOSPHATIDIC ACID; AUTOTAXIN; INFLAMMATION; FIBROSIS; COMPLICATIONS; MECHANISMS; INSIGHTS; INJURY;
D O I
10.18632/aging.204249
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Diabetic nephropathy (DN) is one of the common microvascular complications of diabetes. Autotaxin (ATX) is an enzyme with lysophospholipase D activity, producing lysophosphatidic acid (LPA). LPA signaling has been implicated in renal fibrosis, thereby inducing renal dysfunction. BBT-877 is an orally administered small molecule inhibitor of ATX. However, its effect on DN has not been studied so far. In this study, we investigated the effect of BBT-877, a novel inhibitor of ATX, on the pathogenesis of DN in a mouse model of streptozotocin (STZ)-induced diabetes. BBT-877 treatment significantly reduced albuminuria, albumin-to-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), and glomerular volume compared to the STZ-vehicle group. Interestingly, BBT-877 treatment attenuated hyperglycemia and dyslipidemia in STZ-induced diabetes mice. In the liver, the expression levels of beta-oxidation-related genes such as PPAR alpha and CPT1 were significantly decreased in STZ-induced diabetic mice. However, this effect was reversed by BBT-877 treatment. BBT-877 treatment also suppressed mRNA levels of pro-inflammatory cytokines IL-6, MCP-1, and TNF-alpha and protein levels of fibrotic factors (TGF-beta, fibronectin, CTGF, and collagen type I alpha I (COL1A1)) in the kidneys of STZ-induced diabetic mice. In conclusion, our results indicate that BBT-877 is effective in preventing the pathogenesis of DN by reducing systemic blood glucose levels and inhibiting inflammation and fibrosis in the renal tissue of diabetes mice. These novel findings suggest that inhibition of ATX may be a potential therapeutic target for DN.
引用
收藏
页码:6467 / 6480
页数:14
相关论文
共 64 条
[41]  
Marder Eve, 2016, SCI REP-UK, V7, P563, DOI [DOI https://doi.org/10.1038/s41598-019-57163-7, 10.1038/nrn1949, DOI 10.1038/SREP39419]
[42]   Pharmacologic targeting of the ATX/LPA axis attenuates bleomycin-induced pulmonary fibrosis [J].
Ninou, Ioanna ;
Kaffe, Eleanna ;
Mueller, Stefan ;
Budd, David C. ;
Stevenson, Christopher S. ;
Ullmer, Christoph ;
Aidinis, Vassilis .
PULMONARY PHARMACOLOGY & THERAPEUTICS, 2018, 52 :32-40
[43]   ENPP2 Contributes to Adipose Tissue Expansion and Insulin Resistance in Diet-Induced Obesity [J].
Nishimura, Satoshi ;
Nagasaki, Mika ;
Okudaira, Shinichi ;
Aoki, Junken ;
Ohmori, Tsukasa ;
Ohkawa, Ryunosuke ;
Nakamura, Kazuhiro ;
Igarashi, Koji ;
Yamashita, Hiroshi ;
Eto, Koji ;
Uno, Kansei ;
Hayashi, Naoto ;
Kadowaki, Takashi ;
Komuro, Issei ;
Yatomi, Yutaka ;
Nagai, Ryozo .
DIABETES, 2014, 63 (12) :4154-4164
[44]   Role of lysophosphatidic acid and its receptors in the kidney [J].
Park, Frank ;
Miller, Duane D. .
PHYSIOLOGICAL GENOMICS, 2017, 49 (11) :659-666
[45]  
Pavlyuchenko V. N., 2001, MATH METHOD APPL SCI, V39, P1435, DOI [10.1002/jmri.26616, DOI 10.1002/CCTC.202001179, 10.1002/pola.1120, DOI 10.1002/MMA.7507]
[46]  
Pelli D. G., ENVIRON HEALTH PERSP, V4, P12, DOI [10.1167/4.12.12, DOI 10.1289/EHP3424, 10.1248/bpb.31.159]
[47]   Lysophosphatidic acid and renal fibrosis [J].
Pradere, Jean-Philippe ;
Gonzalez, Julien ;
Klein, Julie ;
Valet, Philippe ;
Gres, Sandra ;
Salant, David ;
Bascands, Jean-Loup ;
Saulnier-Blache, Jean-Sebastien ;
Schanstra, Joost P. .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2008, 1781 (09) :582-587
[48]   Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice [J].
Rancoule, C. ;
Attane, C. ;
Gres, S. ;
Fournel, A. ;
Dusaulcy, R. ;
Bertrand, C. ;
Vinel, C. ;
Treguer, K. ;
Prentki, M. ;
Valet, P. ;
Saulnier-Blache, J. S. .
DIABETOLOGIA, 2013, 56 (06) :1394-1402
[49]   Urinary lysophopholipids are increased in diabetic patients with nephropathy [J].
Saulnier-Blache, Jean-Sebastien ;
Feigerlova, Eva ;
Halimi, Jean Michel ;
Gourdy, Pierre ;
Roussel, Ronan ;
Guerci, Bruno ;
Dupuy, Aude ;
Bertrand-Michel, Justine ;
Bascands, Jean-Loup ;
Hadjadj, Samy ;
Schanstra, Joost P. .
JOURNAL OF DIABETES AND ITS COMPLICATIONS, 2017, 31 (07) :1103-1108
[50]   Pathogenetic mechanisms of diabetic nephropathy [J].
Schena, FP ;
Gesualdo, L .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2005, 16 :S30-S33