מושגי ליבה
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.
תקציר
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:
- 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.
- 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.
סטטיסטיקה
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).
ציטוטים
"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)."