D-serine, a novel uremic toxin, induces senescence in human renal tubular cells via GCN2 activation

The prevalence of chronic kidney disease (CKD), characterized by progressive renal dysfunction with tubulointerstitial fibrosis, is increasing because of societal aging. Uremic toxins, accumulated during renal dysfunction, cause kidney damage, leading to renal deterioration. A recent metabolomic analysis revealed that plasma D-serine accumulation is associated with faster progression of renal dysfunction in CKD patients. However, the causal relationship and the underlying mechanisms remain unclear. Herein, we demonstrated that D-serine markedly induced cellular senescence and apoptosis in a human proximal tubular cell line, HK-2, and primary culture of human renal tubular cells. The former was accompanied by G2/M cell cycle arrest and senescence-associated secretory phenotype, including pro-fibrotic and pro-inflammatory factors, contributing to tubulointerstitial fibrosis. Integrated stress response mediated by the general control nonderepressible 2 played an important role in D-serine-induced tubular cell toxicity and pro-fibrotic phenotypes, accelerating CKD progression and kidney aging. D-serine upregulated the L-serine synthesis pathway. Furthermore, D-serine-induced suppression of tubular cell proliferation was ameliorated by L-serine administration, indicating that D-serine exposure induced an L-serine-deprived state in tubular cells, compensated by L-serine synthesis. Thus, this study unveils molecular mechanisms underlying D-serine-induced tubular damage and pro-fibrotic phenotypes, suggesting that D-serine is a uremic toxin involved in CKD pathogenesis.