Figure 6
From: D-serine, a novel uremic toxin, induces senescence in human renal tubular cells via GCN2 activation
D-serine accelerates CKD via activation of GCN2-mediated ISR. High concentrations of D-serine activate GCN2-mediated ISR, which upregulates ATF4 and CHOP, resulting in cell cycle arrest and apoptosis. Tubular cell senescence, SASP, and apoptosis lead to CKD progression. With increased CKD severity, plasma D-serine concentration rises, creating a vicious cycle of progressively greater D-serine toxicity and renal failure. On the other hand, ATF4 up-regulates L-serine synthesis response, which may partially contribute to the amelioration of the “pseudo-” L-serine starvation state. Consistently, L-serine supplementation abrogated cellular toxicity induced by D-serine.
