Tubulointerstitial injury is an important determinant of chronic kidney disease progression, yet treatment is limited. Accordingly, we derived a chronic kidney disease progression signature based on aging and disease in Col4a3^–/– mice, a model associated with proteinuria and progressive loss of kidney function. Computational drug repurposing with the Connectivity Map identified vorinostat, a lysine deacetylase inhibitor, as a candidate treatment to reverse progression signature gene expression. Vorinostat administration significantly increased the lifespan of Col4a3^–/– mice and attenuated tubulointerstitial fibrosis and JNK phosphorylation in the kidneys of Col4a3^–/– mice. In vitro, vorinostat reduced albumin- and angiotensin II-induced activation of canonical mitogen-activated protein kinases in kidney tubular epithelial cells. Finally, a subset of murine progression signature genes was differentially expressed across kidney transcriptomic data from patients with focal segmental glomerulosclerosis, IgA nephropathy, and diabetic nephropathy. Thus, our findings suggest that lysine deacetylase inhibition may be a novel treatment to chronic kidney disease associated with proteinuria and progressive tubulointerstitial injury.

肾小管间质损伤是慢性肾脏疾病进展的重要决定因素，但治疗受到限制。因此，我们基于Col4a3 ^{– / –}小鼠的衰老和疾病得出了慢性肾脏疾病进展的特征，该模型与蛋白尿和肾脏功能进行性丧失有关。用Connectivity Map重新设计的计算药物将伏立诺他（一种赖氨酸脱乙酰基酶抑制剂）鉴定为逆转进展签名基因表达的候选药物。伏立诺他管理显著上升的寿命COL4A3 ^{- / -}小鼠和减毒间质纤维化和JNK的磷酸化在肾脏COL4A3 ^{- /–}老鼠。在体外，伏立诺他降低了肾小管上皮细胞中白蛋白和血管紧张素II诱导的经典丝裂原活化蛋白激酶的活化。最后，鼠病程特征基因的子集在局灶性节段性肾小球硬化症，IgA肾病和糖尿病肾病患者的肾脏转录组数据中差异表达。因此，我们的发现表明，抑制赖氨酸脱乙酰基酶可能是一种与蛋白尿和进行性肾小管间质损伤相关的慢性肾脏疾病的新型治疗方法。