Research Paper Volume 14, Issue 16 pp 6467—6480
Effect of BBT-877, a novel inhibitor of ATX, on a mouse model of type 1 diabetic nephropathy
- 1 Department of Marine Bio and Medical Science, Hanseo University, Seosan, Korea
- 2 College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Korea
- 3 Bridge Biotherapeutics Incorporation, Seongnam, Korea
- 4 Boostimmune Therapeutics Incorporation, Seongnam, Korea
- 5 Department of Rehabilitation Medicine, Gachon University, Incheon, Korea
- 6 Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
Received: February 1, 2022 Accepted: August 17, 2022 Published: August 26, 2022
https://doi.org/10.18632/aging.204249How to Cite
Copyright: © 2022 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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 β-oxidation-related genes such as PPAR α 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-α and protein levels of fibrotic factors (TGF-β, fibronectin, CTGF, and collagen type Ι alpha Ι (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.