Identification of Sodium-Coupled Monocarboxylate Transporters as Novel D-Serine Transporters in the Kidney

แนวคิดหลัก

Sodium-coupled monocarboxylate transporters (SMCTs) are identified as novel D-serine transporters in the kidney, complementing the previously known D-serine transporter ASCT2. The differential expression and transport kinetics of these two systems explain the dynamics of D-serine as an emerging biomarker of kidney diseases.

บทคัดย่อ

The study aimed to investigate the transport systems for D-amino acids, particularly D-serine, in the kidney. Using a multi-omics approach, the authors identified two D-serine transport systems in the renal proximal tubules:

1. ASCT2 (SLC1A5):

• ASCT2 is localized at the apical membrane of all proximal tubular segments.
• ASCT2 transports D-serine with high affinity (Km 167 μM) but low stereoselectivity.

2. Sodium-coupled monocarboxylate transporters (SMCTs):

• SMCT1 (SLC5A8) is mainly expressed in the S3 segment, while SMCT2 (SLC5A12) is in the S1 and S2 segments.
• SMCTs transport D-serine with lower affinity (Km 3.39 mM for SMCT1) but higher stereoselectivity compared to ASCT2.

In normal kidneys, both ASCT2 and SMCTs contribute to D-serine reabsorption, with SMCTs playing a more dominant role due to their higher expression levels.

In the ischemia-reperfusion injury (IRI) model of acute kidney injury (AKI), the expression of SMCTs decreases dramatically, while ASCT2 increases. This shift leads to enhanced D-serine reabsorption by ASCT2, resulting in the elevated plasma D-serine levels observed in AKI and chronic kidney disease (CKD).

The distinct transport kinetics and expression patterns of ASCT2 and SMCTs explain the unique enantiomeric profiles of serine in the body fluids during kidney diseases, highlighting the importance of non-canonical substrate transport by membrane transporters.

สถิติ

Plasma D-/L-serine ratio increased in a time-dependent manner from 4 to 40 hours after ischemia-reperfusion injury.
The elevation of plasma D-/L-serine ratios at early time points (4h - 8h) was due to a sharp decrease of the L-isomer, while the rise at late time points (20h - 40h) was a result of a continuous acceleration of the D-isomer.
Urinary D-/L-serine ratios were drastically decreased at early ischemia-reperfusion injury (4h - 8h).

คำพูด

"Mammals acquire D-serine by biosynthesis via serine racemase function (Wolosker et al., 1999) and absorption from the diet and gut microbiota presumably via intestinal transport system(s) (Sasabe and Suzuki, 2018; Nakade et al., 2018; Gonda et al., 2023)."
"Silbernagl et al. also suggested that ASCT2 is not (or not only) a D-serine transporter at S3 segment (Silbernagl et al., 1999)."
"Kinetics analysis of D-serine transport revealed the high affinity by ASCT2 (Km 167 μM) (Foster et al., 2016) and low affinity by SMCT1 (Km 3.39 mM; Figure 5E)."

ข้อมูลเชิงลึกที่สำคัญจาก

A multi-hierarchical approach reveals D-serine as a hidden substrate of sodium-coupled monocarboxylate transporters

by Wiriyasermku... ที่ www.biorxiv.org 08-10-2020

https://www.biorxiv.org/content/10.1101/2020.08.10.244822v3

สอบถามเพิ่มเติม

What are the potential implications of the differential expression and transport kinetics of ASCT2 and SMCTs in the context of kidney disease progression and therapeutic interventions

The differential expression and transport kinetics of ASCT2 and SMCTs in the context of kidney disease progression and therapeutic interventions have significant implications. In kidney diseases, such as acute kidney injury (AKI) and chronic kidney disease (CKD), the alterations in the expression levels of these transporters can impact the reabsorption and handling of D-serine in the kidney.

Kidney Disease Progression: The upregulation of ASCT2 and downregulation of SMCTs observed in AKI and CKD can lead to an imbalance in D-serine reabsorption. This imbalance may contribute to the accumulation of D-serine in the blood, which has been associated with kidney damage and dysfunction. Understanding the roles of ASCT2 and SMCTs in D-serine transport can provide insights into the mechanisms underlying kidney disease progression.

Therapeutic Interventions: Targeting ASCT2 and SMCTs could be a potential therapeutic strategy for managing kidney diseases. Modulating the expression or activity of these transporters may help regulate D-serine levels and mitigate kidney damage. For example, developing specific inhibitors or activators of ASCT2 and SMCTs could offer novel treatment options for kidney diseases by restoring D-serine homeostasis.

Precision Medicine: The differential expression of ASCT2 and SMCTs in kidney diseases highlights the importance of personalized treatment approaches. By understanding the individual variations in transporter expression and kinetics, clinicians can tailor interventions to target specific transport systems based on the patient's profile. This personalized approach could improve treatment outcomes and minimize adverse effects.

How might the gut microbiome-derived D-serine contribute to the dynamics of D-serine in the body and the development of kidney diseases

The gut microbiome-derived D-serine can play a significant role in the dynamics of D-serine in the body and the development of kidney diseases.

Contribution to D-Serine Levels: D-serine produced by the gut microbiome can enter the circulation and affect the overall D-serine levels in the body. The balance between endogenous D-serine production, dietary intake, and gut microbiome-derived D-serine can influence the systemic D-serine concentrations, including those in the kidney.

Impact on Kidney Function: Imbalances in gut microbiome-derived D-serine levels may impact kidney function and contribute to the development or progression of kidney diseases. High levels of circulating D-serine, whether from endogenous or exogenous sources, can affect renal function and potentially lead to kidney damage.

Therapeutic Targets: Targeting the gut microbiome-derived D-serine production could be a potential therapeutic strategy for managing kidney diseases. Modulating the composition of the gut microbiome or inhibiting specific pathways involved in D-serine production by gut bacteria may help regulate systemic D-serine levels and protect kidney health.

Research Opportunities: Further research into the interactions between gut microbiome-derived D-serine and kidney function could uncover novel pathways and mechanisms underlying kidney diseases. Understanding the role of the gut microbiome in D-serine dynamics may open up new avenues for therapeutic interventions and personalized treatment strategies.

Could the understanding of D-serine transport systems in the kidney provide insights into the role of D-amino acids in other physiological processes and diseases beyond the kidney

The understanding of D-serine transport systems in the kidney can provide valuable insights into the role of D-amino acids in other physiological processes and diseases beyond the kidney.

Neurological Disorders: D-serine, as an obligatory co-agonist of N-methyl-D-aspartate receptors (NMDARs) in the brain, plays a crucial role in synaptic transmission and plasticity. Dysregulation of D-serine levels has been implicated in neurological disorders such as schizophrenia, Alzheimer's disease, and epilepsy. Understanding the transport mechanisms of D-serine in the kidney may shed light on its involvement in these neurological conditions.

Metabolic Disorders: D-amino acids, including D-serine, have been linked to metabolic disorders such as diabetes and obesity. The transport systems responsible for D-serine reabsorption in the kidney could be interconnected with metabolic pathways and contribute to the development of metabolic diseases. Studying D-serine transport systems may uncover novel links between D-amino acids and metabolic health.

Cancer Biology: Emerging evidence suggests that D-amino acids play a role in cancer progression and metastasis. The transporters involved in D-serine transport in the kidney may have implications for cancer biology, particularly in the context of amino acid metabolism and tumor growth. Investigating the transport systems of D-serine could provide insights into the role of D-amino acids in cancer development and treatment strategies.