Gene signature-guided drug screening identified narciclasine as a potential therapeutic for interstitial fibrosis of the kidney

Abstract

Introduction: Chronic Kidney Disease (CKD) is marked by progressive tubulointerstitial fibrosis (TIF), a pathological feature insufficiently addressed by existing therapies.

Methods: To identify drugs with potential to halt TIF progression, we constructed a TIF-specific gene expression signature using published human CKD kidney transcriptome data and employed the small molecule perturbant library LINCS L1000 database for a high-throughput screening of compounds capable of reversing the expression of TIF-related genes.

Results: Narciclasine, a natural compound derived from the Narcissus (amaryllis) plant, was identified as a top compound which significantly reversed the gene expression signature of TIF. Administration of narciclasine not only significantly prevented inflammation and fibrotic lesions induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury but also delayed the progression of established TIF induced by unilateral ureteral obstruction. Furthermore, in the 5/6 nephrectomy-induced CKD model, narciclasine significantly lowered serum creatinine, reduced proteinuria, and alleviated TIF and inflammation.

Conclusions: Mechanistically, narciclasine reversed the failed-repair phenotype of tubular epithelial cells and inhibited fibroblasts proliferation and activation, at least partially via inhibiting the activation of NF-κB signaling. Our findings suggest that narciclasine should be further investigated as a promising drug candidate to attenuate CKD.

Keywords: chronic kidney disease; gene expression signatures; high-throughput drug screening; narciclasine; renal interstitial fibrosis.