Serine Metabolism Breakdown Drives Kidney Aging — And Fixing It May Slow CKD
Scientists identify a glycolysis-serine axis controlled by PGK1 that governs podocyte aging, offering a new therapeutic target for chronic kidney disease.
Summary
Researchers discovered that angiotensin II suppresses the enzyme PGK1 in podocytes — kidney filtration cells — by activating the transcription factor FOXA1. This reduces L-serine biosynthesis from the glycolytic intermediate 3-phosphoglycerate, triggering mitochondrial dysfunction, actin cytoskeleton collapse, lipid accumulation, and cellular senescence. The serine deficit also shifts sphingolipid metabolism toward toxic deoxysphingolipids via the PI3K/AKT pathway. Restoring serine levels or re-expressing PGK1 in mouse CKD models reversed these effects. PGK1 was also found to physically stabilize podocyte cytoskeleton via interaction with keratin KRT1, revealing a dual metabolic-structural role for this enzyme.
Detailed Summary
Chronic kidney disease (CKD) affects hundreds of millions of people worldwide, and the progressive loss of podocytes — the specialized, non-regenerating filtration cells of the glomerulus — is a central driver of kidney scarring and decline. This study from Wuhan University, published in Nature Communications, uncovers a previously unrecognized metabolic pathway linking impaired glycolysis, serine deficiency, and accelerated podocyte senescence.
The research team found that angiotensin II (Ang II), a key mediator of hypertensive kidney damage, suppresses expression of phosphoglycerate kinase 1 (PGK1) through the transcription factor FOXA1. PGK1 normally catalyzes conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate (3-PG) during glycolysis — a step that also feeds the serine biosynthesis pathway via PHGDH and PSAT1. By downregulating PGK1, Ang II depletes intracellular L-serine, a finding confirmed by metabolomics in podocytes exposed to Ang II, high glucose, or adriamycin.
Serine deficiency had wide-ranging consequences. Electron microscopy, oxygen consumption rate (OCR) measurements, and membrane potential assays showed severe mitochondrial damage. Phalloidin staining revealed actin cytoskeleton collapse, and Oil Red O staining confirmed lipid accumulation. Critically, beta-galactosidase staining and elevated SASP cytokines (IL-1β, IL-6) confirmed that serine loss accelerates cellular senescence. The mechanism involves a shift in sphingolipid metabolism: with insufficient serine, serine palmitoyl-transferase (SPT) uses alanine as a substitute, generating cytotoxic deoxysphingolipids (doxSA, doxSO) that impair the PI3K/AKT survival pathway and worsen senescence. Inhibiting SPT activity reversed these effects.
Supplementing L-serine or overexpressing PGK1 in both mouse (MPC-5) and human podocyte cell lines restored mitochondrial function, cytoskeletal integrity, and reduced senescence markers. In CKD mouse models (Ang II infusion and adriamycin nephropathy), podocyte-specific PGK1 overexpression reduced proteinuria, glomerulosclerosis, and podocyte loss. A novel interaction between PGK1 and keratin KRT1 was also identified, suggesting that PGK1 plays a structural role in podocyte cytoskeletal maintenance independent of its enzymatic function.
The study positions the PGK1–serine axis as a tractable therapeutic target. Both exogenous L-serine supplementation and gene-based PGK1 restoration showed efficacy in preclinical models, suggesting multiple intervention points. Caveats include the reliance on rodent and cell-line models, the complexity of translating metabolic interventions to clinical settings, and the need to fully delineate the FOXA1–PGK1 regulatory network in human disease contexts.
Key Findings
- Ang II suppresses PGK1 via FOXA1, depleting intracellular L-serine in podocytes across multiple injury models.
- Serine deficiency triggers toxic deoxysphingolipid production via SPT, impairing PI3K/AKT signaling and accelerating senescence.
- L-serine supplementation reverses mitochondrial dysfunction, actin collapse, lipid accumulation, and SASP in podocytes.
- Podocyte-specific PGK1 overexpression reduces proteinuria and glomerulosclerosis in CKD mouse models.
- PGK1 physically interacts with KRT1 to stabilize the podocyte cytoskeleton, revealing a structural role beyond glycolysis.
Methodology
The study used in vitro mouse (MPC-5) and human podocyte cell lines, amino acid metabolomics, untargeted lipidomics, RNA-seq of human HN kidney biopsies (GEO: GSE166239), transmission electron microscopy, and OCR/ECAR assays. In vivo validation employed Ang II infusion and adriamycin nephropathy CKD mouse models with podocyte-specific PGK1 overexpression.
Study Limitations
Findings are primarily based on rodent models and immortalized cell lines; direct human clinical evidence is absent. The FOXA1–PGK1 transcriptional mechanism requires further validation in primary human podocytes and patient-derived tissue. Long-term safety and dosing of L-serine supplementation for kidney protection have not been established.
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