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

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.

Lysophosphatidic Acid Induces Podocyte Pyroptosis in Diabetic Nephropathy by an Increase of Egr1 Expression via Downregulation of EzH2

“…Hyperglycemia can change podocyte phenotype by inducing the loss of nephrin, altering the production/degradation of extracellular matrix components, and enhancing pro-trophic cytokine-modifying growth factors [ 28 ]. However, LPA has been recently identified as another important factor in DN pathogenesis [ 12 , 13 , 14 , 15 ]. Zhang et al reported that LPAR1/3 inhibition in type 2 diabetic mice restored podocyte marker expression and the podocyte number in glomeruli [ 15 ]; however, the underlying mechanisms remain unclear.…”

“…Moreover, patients with diabetes experiencing DN had significantly enhanced urinary levels of LPA and LPC when compared with patients without DN [ 11 ]. Additionally, several previous studies, including by our research group, have shown that inhibition of LPA signaling can attenuate DN-associated fibrosis and renal inflammation in diabetic animal models [ 12 , 13 , 14 , 15 ]. Although the antagonism of LPAR1/3 protects against podocyte loss in endothelial nitric oxide synthase (eNOS) −/− db/db mice, a type 2 diabetes model [ 15 ], the role of LPA/LPAR1 signaling in podocyte damage during DN remains unexplored.…”

Breviscapine alleviates podocyte injury by inhibiting NF-κB/NLRP3-mediated pyroptosis in diabetic nephropathy

“…Diabetes was induced by intraperitoneal (i.p.) injections of STZ (Aladdin, Shanghai, China) at a dose of 50 mg/kg for 5 consecutive days, as previously described ( Lee et al, 2022 ; Song et al, 2022 ; Zhong et al, 2019 ). Mice with blood glucose >16.7 mmol/L were considered diabetic 3 days after the injection ( He et al, 2013 ).…”

Diabetic Nephropathy and Gaseous Modulators

“…One of the hallmarks of DN is the progressive expansion of the mesangial matrix, which is developed by the accumulation of the components of the extracellular matrix (ECM) [5]. Alteration in local gene expression of humoral growth factors, such as transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), and platelet-derived growth factor (PDGF), may promote elevated production of the ECM component, e.g., fibronectin and collagen IV, or decreased degradation by matrix metalloproteinases, e.g., MMP-1 and MMP-2, in DN [6][7][8].…”