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

Abstract

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.

Gut microbiota–derived D-serine protects against acute kidney injury

“…Several studies have reported the nephrotoxicity of D-serine (19). Although a peritoneal injection of 400-800 mg/kg D-serine induced tubular damage in rats (20,22), Okada et al (25) reported that 20 mM D-serine activated general control nonderepressible 2 kinase, thus leading to cellular senescence in human tubular cells. In agreement with those studies, we observed D-serine cytotoxicity in the current study.…”

Monitoring of the influence of long‐term oxidative stress and ischemia on the condition of kidneys using solid‐phase microextraction chemical biopsy coupled with liquid chromatography–high‐resolution mass spectrometry

“…D‐amino acids have been recently discovered as naturally occurring in human stereoisomers of well‐known l ‐amino acids, and are now considered to serve as potential biomarkers, especially in renal pathophysiology. Several chiral metabolomics studies have reported on the impact of d ‐serine on kidney dysfunction [47–49]. Hesaka et al.…”

“…Okada et al. revealed that d ‐serine accumulation prompts renal tubular cells senescence and apoptosis, which drastically impair kidney function and accelerate CKD progression [49].…”

d-Amino acids and kidney diseases

“…In contrast, administration of d-alanine, which can also produce hydrogen peroxide upon oxidation by DAO, does not induce kidney injury in rodents, obscuring the causal relationship of DAO with kidney injury [37,39]. Using kidney tubular cell lines (HK-2) and primary cultures of kidney tubular cells, one study suggested the toxic mechanism of higher doses of d-serine as the induction of cell cycle arrest, pro-inflammatory response, and apoptosis via effector molecules of ER stress [40]. Higher doses of d-serine have been used in some clinical studies in schizophrenia and cerebellar ataxia [41,42], as a potential activator of NMDAR.…”