Renal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Sydney, Australia.
Sydney Medical School Northern, University of Sydney, NSW, Sydney, Australia.
Sci Rep. 2018 Jun 21;8(1):9423. doi: 10.1038/s41598-018-27462-6.
Diabetic nephropathy is characterised by the excessive amount of extracellular matrix in glomeruli and tubulointerstitial space. Lysyl oxidase-like 2 (LOXL2) is elevated in renal fibrosis and known to play key roles in ECM stabilisation by facilitating collagen cross-links, epithelial to mesenchymal transition and myofibroblast activation. Thus, targeting LOXL2 may prove to be a useful strategy to prevent diabetic nephropathy. We explored the renoprotective effect of a selective small molecule LOXL2 inhibitor (PXS-S2B) in a streptozotocin-induced diabetes model. Diabetic mice were treated with PXS-S2B for 24 weeks and outcomes compared with untreated diabetic mice and with telmisartan treated animals as comparator of current standard of care. Diabetic mice had albuminuria, higher glomerulosclerosis scores, upregulation of fibrosis markers and increased renal cortical LOXL2 expression. Treatment with PXS-S2B reduced albuminuria and ameliorated glomerulosclerosis. This was associated with reduced expression of glomerular fibronectin and tubulointerstitial collagen I. The renoprotective effects of both PXS-S2B and telmisartan were more marked in the glomerular compartment than in the tubulointerstitial space. The study reveals that LOXL2 inhibition was beneficial in preserving glomerular structure and function. Thus, LOXL2 may be a potential therapeutic target in diabetic nephropathy.
糖尿病肾病的特征是肾小球和肾小管间质空间中细胞外基质的含量过多。赖氨酰氧化酶样 2（LOXL2）在肾纤维化中升高，已知通过促进胶原蛋白交联、上皮细胞向间充质转化和肌成纤维细胞激活，在 ECM 稳定化中发挥关键作用。因此，靶向 LOXL2 可能是预防糖尿病肾病的一种有用策略。我们在链脲佐菌素诱导的糖尿病模型中探索了选择性小分子 LOXL2 抑制剂（PXS-S2B）的肾脏保护作用。用 PXS-S2B 治疗糖尿病小鼠 24 周，并与未治疗的糖尿病小鼠和作为当前标准护理比较剂的替米沙坦治疗动物的结果进行比较。糖尿病小鼠有白蛋白尿，肾小球硬化评分更高，纤维化标志物上调，肾皮质 LOXL2 表达增加。用 PXS-S2B 治疗可减少白蛋白尿并改善肾小球硬化。这与肾小球纤维连接蛋白和肾小管间质胶原 I 的表达减少有关。PXS-S2B 和替米沙坦的肾脏保护作用在肾小球比在肾小管间质空间更为显著。该研究表明，LOXL2 抑制有益于保持肾小球结构和功能。因此，LOXL2 可能是糖尿病肾病的一个潜在治疗靶点。
