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Role of Plasma D-serine in Progression of Chronic Kidney Disease

The Excretory System and Chronic Kidney Disease

The kidneys and bladder are part of the excretory system, which is responsible for filtering and removing waste from the blood. Blood is filtered in the nephrons of the kidney, which are lined with renal epithelial cells that reabsorb water and other useful compounds like amino acids. These epithelial cells also ensure that waste products are removed and collected in the fluid that is expelled from the kidneys – the urine. Urine then transits through one of two ureters into the bladder, from where it is excreted from the body.

Chronic kidney disease develops when the kidneys become damaged and do not properly function, leading to a buildup of waste products in the body, which can contribute to other health issues. Over time, patients with chronic kidney disease lose kidney function and may develop kidney failure. Once the disease has progressed to end-stage kidney disease, dialysis or a kidney transplant is typically required.

One of the damaging side effects of chronic kidney disease is the buildup of uremic toxins, damaging compounds that are usually filtered by the kidneys, but in the setting of kidney dysfunction, these compounds build up in the body and can cause a number of negative effects. Discussed below is a study published in Scientific Reports (opens in new tab) demonstrating the mechanism by which D-serine acts as a uremic toxin.

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Lifeline Renal Cells in Chronic Kidney Disease Research

Amino acids are chiral molecules that can take one of two forms, called L and D. In particular, the form of the amino acid serine normally found in the plasma is L-serine. Previous research has hinted at a role for plasma D-serine in increasing the risk for progression to end-stage kidney disease in patients with chronic kidney disease. In a 2017 study, Okada and colleagues (opens in new tab) investigated whether D-serine exerts negative effects on proximal renal tubular cells and the potential mechanism by which it does so, namely through stress pathways.

The authors first examined the effects of D-serine on renal epithelial cells. Using HK-2 cells (an immortalized human proximal tubular cell line) and Lifeline normal human renal epithelial cells, the group showed that treatment with D-serine (and not L-serine) decreased cell proliferation and increased apoptosis. Further investigation demonstrated that D-serine treatment induced cell cycle arrest at the G2/M phase, illustrated by upregulation of phosphorylated histone H3 (a G2/M marker) and p21 (a cell cycle inhibitor). Additionally, the authors found increased expression of senescence markers following D-serine treatment, including p16, senescence-associated b-galactosidase, and g-H2AX. Markers of the senescence-associated secretory phenotype were also present following D-serine treatment, including IL-6 and IL-8.

To further define the mechanism by which D-serine induces renal tubular cell senescence, the authors investigated its effects on the integrated stress response (ISR). In the absence of L-amino acids, general control nondepressible 2, or GCN2, is activated and induces downstream stress signaling pathways. As hypothesized, the authors observed GCN2-dependent activation of ISR pathways by D-serine in HK-2 cells and Lifeline normal human renal epithelial cells. Finally, the authors found that D-serine activated the L-serine synthesis pathway and addition of L-serine itself ameliorated that negative effects of D- serine on cells.

Together, the results of this study demonstrate that D-serine is a uremic toxin that contributes to the pathogenesis of chronic kidney disease.

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