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• W3039761446 abstract "Nature is full of miracles. One such phenomenon is the existence of enantiomers, molecules that are mirror images of each other. Chirality is widespread and stereoisomers exhibit similar physical and chemical properties, however, are not identical and may have strikingly different physiological effects. One example is Thalidomide, a sedative marketed as Contergan® from 1957 to 1961 by the German company Chemie Grünenthal. The racemate caused abnormalities in children being born to mothers using this drug against morning sickness during pregnancy. Later, it turned out that the L-enantiomer was a good sedative, whereas the D-form was harmful. Here, we will focus on D-serine, a non-essential amino acid and enantiomer of L-serine. It is emerging as a potential biomarker for kidney disease that can be detected in both blood and urine. Endogenous D-serine has a neuromodulatory role. It is vital for synapse development and for physiological function of the nervous system. D-serine was proven to be a ligand for the glycine site of the N-methyl D-Aspartate (NMDA) receptor and is synthesized from L-serine in the brain.1 As a potent agonist of the receptor, D-serine is considered to be a potential therapeutic agent in schizophrenia and major depressive disorders,1 linked to hypo-function of NMDA receptor-mediated signalling.2 Notably, in a clinical study with patients at high risk of schizophrenia, 10% of the participants in the group receiving D-serine orally were withdrawn because of massive renal damage, which has been attributed to the treatment.3 Measurements of D-enantiomers are challenging because they share the same physical properties with the L-enantiomers.1 Mothet et al emphasized the importance that researchers validate the specificity of their detection through suitable controls.1 Nowadays, 2D high-performance liquid chromatography (HPLC) is one of the methods of choice for a precise measurement of D-amino acids. Nephropathies are characterized as loss of kidney function due to renal disease or kidney damage.4 Many publications, issued recently in Acta Physiologica, cover diverse areas of the extensive field of kidney research. Among these are studies about renal haemodynamics,5-7 about potential prevention of acute kidney injury8 or promising treatment of chronic kidney disease.9, 10 Investigations to understand, diagnose and treat renal diseases and renal damage are necessary and important for patients, society and public health care.4 Moreover, biomarkers for fast and clear-cut detection of origin and location of renal damage still need to be established. D-serine levels in blood and urine are sensitive to the presence of kidney dysfunction of different origins. Studies published in recent years added clarity to the nature of D-serine in relation to the kidney. In a longitudinal cohort study of patients with advanced CKD, Kimura et al examined the connection between chiral amino acids and kidney function, comorbidities and prognosis. Higher levels of D-serine in blood were significantly associated with the progression of CKD to end-stage kidney failure.11 Thus, the study demonstrated a clinical potential of D-serine as biomarker in CKD. Hesaka et al also studied the intra-body dynamics of D-serine in a cohort of 11 patients with CKD. The plasma level of D-serine correlated well with inulin clearance, a gold standard for determining glomerular filtration rate (GFR). This correlation was compatible with those of the conventional kidney disease markers, serum creatinine and cystatin C.12 Blood levels of D-serine appeared not to be affected by clinical factors, such as body surface area, age and sex.12 Furthermore, fractional excretion of D-serine was restricted within a certain range in healthy volunteers, whereas it had a broader range in CKD patients and it provided information independent of the GFR.12 Noteworthy, neither D-serine blood level nor its urinary dynamics alone, but the combination of both effectively distinguished CKD from non-CKD patients.12 Several animal studies have investigated the dynamics of D-serine in connection with acute kidney injury (AKI). In a mouse model of cisplatin-induced AKI, a positive correlation between serum D- to L-serine ratio and both serum creatinine and BUN was detected.13 What is more, the variation of serum D-serine levels observed in the cisplatin-treated group reflected the individual variability in renal damage.13 In an ischemia/reperfusion AKI model in mice, Sasabe et al reported a correlation between the levels of D-serine in the systemic circulation with that of creatinine. Furthermore, the authors demonstrated that the ratio of serine enantiomers in the urine may serve as a sensitive biomarker in the early detection of acute kidney disease.14 The significantly reduced urinary D- to L-serine ratio in treated mice could detect ischemia earlier than kidney injury molecule 1 (Kim-1) or neutrophil gelatinase-associated lipocalin (Ngal).14 Changes in D-serine levels and D-serine accumulation in the systemic circulation in kidney diseases may be a consequence of the reduction of the GFR.14 However, changes in the tubular reabsorption or in its enzymatic regulation might also play a significant role. Therefore, to answer the question whether D-serine represents a powerful biomarker for CKD and AKI, more knowledge is needed about its regular turnover. After glomerular filtration, the kidney reabsorbs amino acids in the proximal tubule with chiral selectivity.15 A large amount of the filtered L-serine is reabsorbed in the nephron. Under physiological conditions, the excretion of D-serine is much greater than that of L-Serine. In a mouse cisplatin model and HEK293 cell culture model, Suzuki et al demonstrated that the neutral amino acid transporter alanine–serine–cysteine-1 (Asc-1) could serve as a supplementary amino-acid transporter under conditions where proximal tubules were injured. Asc-1 is induced in the distal tubules or the collecting ducts after proximal tubular damage and is capable of high-affinity transport of D-serine.13 This consequently might lead to serum D-serine accumulation. The exact mechanism of D-serine reabsorption in nephrons, however, needs further investigation. The level of D-serine in the body is not only regulated by its excretion through the urinary tract but also by the enzymes serine racemase (SR) and D-amino acid oxidase (DAAO). While SR catalyses the synthesis of D-serine, both SR and DAAO can mediate its degradation.1 In ischemia/reperfusion injury (IRI) model in mice, Sasabe et al demonstrated that knock out of SR in mice reduced the basal level of D-serine. However, no alteration of serine enantiomers ratio was observed. The results indicated that serine racemase did not trigger the derangement of serine enantiomers caused by the IRI.14 DAAO-mediated degradation of D-serine also controls D-serine levels. DAAO-null mice exhibit a significant accumulation of D-serine in serum.14 Therefore, tubular DAAO is considered to degrade reabsorbed D-serine, from the luminal side to avoid its passage to the basolateral side. The reabsorbed D-serine in renal tubules is metabolized by DAAO into hydroxypyruvate, ammonia and hydrogen peroxide.15 However, treatment with cisplatin, as a model to induce AKI in mice, did not significantly alter renal DAAO activity.13 This finding implied that changes in serum D-serine level were not only attributed to DAAO.13 In contrast, in an IRI mouse model, renal DAAO activity was reduced, indicating that serum D-serine increase is at least partly associated with decreased DAAO activity.14 Moreover, in DAAO-null mice, IRI led to a more severe injury of the proximal tubules than in wild-type mice, suggesting a renoprotective role of DAAO.14 Several studies reported that the administration of exogenous D-serine causes nephrotoxicity. Due to the production of cytotoxic hydrogen peroxide, DAAO is suspected to be involved in the D-serine induced nephrotoxicity.15 Moreover, rats treated with intraperitoneal D-serine injection indicated that DAAO-mediated D-serine metabolism lowered the concentration of intracellular glutathione, a scavenger of reactive oxygen species (ROS).15 Exceeding the normal physiological range of ROS may result in cellular dysfunction, activation of a damage response and cell death.16 In contrast to these data, in IRI-induced renal pathology in mice, as mentioned above, DAAO had a rather protective effect.14 How can that be? Are we faced with a species difference? It is still uncertain, but we have to look further. In vitro studies using renal tubular cell lines indicated a molecular mechanism of D-serine-mediated toxicity that is independent from DAAO.17 In these models, D-serine induced the integrated stress response, cell-cycle arrest and apoptosis.17 Finally, a study by Nakade et al holds an opposing viewpoint regarding the nephrotoxic effect of D-serine. The study examined the role of D-amino acids in association with gut microbiota in AKI. In a mouse IRI model, gut microbiota and oral administration of D-serine did not contribute but protected against tubular damage.18 The conclusion was based on histological assessment of the tubules. However, the levels of serum creatinine and BUN, as well as the extent of interstitial fibrosis were similar between the treated and the control groups. Kidney fibrosis is known to play a major role in the development and progression of CKD.19 The microbiome in the human body is involved in a variety of functions,20, 21 and has an influence on multiple aspects of host physiology.22 Thus, kidney function might be greatly dependent on the microbiome, and vice versa, and D-serine might induce different pathways in gut and kidney. In summary, biomarkers can be helpful in detecting pathological changes at an early stage of a disease. Diverse biomarkers for AKI and CKD have been identified and characterized. D-serine may contribute as a potential biomarker for the comprehensive management of nephropathies. It has been well described that kidney dysfunction leads to derangement of the levels of L- vs. D-serine in blood and urine. Many aspects of D-serine turnover such as filtration & reabsorption, synthesis & degradation have to be considered to bring more clarity to the mystery, whether D-serine in the plasma contributes to the damage of the kidney, is it a result of that, or both. Answering the question how D-serine contributes to renal pathology, remains quite exciting. None." @default.
• W3039761446 created "2020-07-10" @default.
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• W3039761446 date "2020-07-18" @default.
• W3039761446 modified "2023-10-01" @default.
• W3039761446 title "D‐serine—A useful biomarker for renal injury?" @default.
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• W3039761446 doi "https://doi.org/10.1111/apha.13531" @default.
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