Impaired glycolysis-derived serine metabolism as a key driver of podocyte injury with senescence

Sep 30, 2026

Impaired glycolysis-derived serine metabolism underlies podocyte injury with senescence in chronic kidney disease. The study examines how angiotensin II (Ang II) disrupts L-serine synthesis and podocyte homeostasis, focusing on phosphoglycerate kinase 1 (PGK1) control via the transcription factor FOXA1. In vivo and in vitro models show that Ang II decreases PGK1, reducing L-serine biosynthesis, driving mitochondrial dysfunction, and elevating cellular senescence. Restoring L-serine or PGK1 rescues mitochondrial function and senescence-associated phenotypes, and PGK1 is linked to cytoskeletal stability through interaction with KRT1.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Background

Podocyte senescence in CKD

Angiotensin II and glomerular injury

Link to glycolysis and metabolic intermediates

Mechanistic Rationale

3-PG as a precursor for L-serine

PGK1 as a central regulator of serine metabolism

Study Approach and Key Findings

Ang II regulation of PGK1 and FOXA1

Effects on mitochondrial function and senescence

Rescue by L-serine supplementation or PGK1 enhancement

PGK1 interaction with KRT1 and cytoskeletal integrity

Article [https://doi.org/10.1038/s41467-025-66850-1](https://doi.org/10.1038/s41467-025-66850-1) Impaired glycolysis-derived serine metabolism as a key driver of podocyte injury with senescence Received: 11 March 2025 | Accepted: 17 November 2025 | | --- | | | | Check for updates | Hongtu Hu1,2,3, Zijing Zhu1,2,3, Lanlan Li 1,2,3, Jijia Hu1,2,3, Qian Yang1,2, Zhuan Peng1,2, Weiwei Li1,2, Xiaofei Cui1,2, Yanqin Fan1,2, Wenjie Chen1,2, Wei Liang 1,2 , Zhaowei Chen 1,2 & Guohua Ding 1,2 Chronic kidney disease (CKD) is a major health issue, with podocyte injury with senescence playing a central role inglomerulosclerosis. This study investigates the link between glycolysis-derived serine metabolism and podocyte injury with senescence, focusing on the role of phosphoglycerate kinase 1 (PGK1) in the regulation of L-serine synthesis and podocyte homeostasis. Using in vivo and in vitro models, we examined the effects of angiotensin II (Ang II)-induced metabolic dysregulation on serine metabolism and its impact on podocyte function. The results demonstrate that Ang II downregulates PGK1 expression through the transcription factor FOXA1, leading to reduced L-serine biosynthesis, mitochondrial dysfunction, and increased cellular senescence in podocytes. Supplementing with L-serine or enhancing PGK1 expression in podocytes alleviated these pathological changes, restored mitochondrial function, and reduced senescence-associated phenotypes in CKD mouse models. Moreover, PGK1 was found to interact with keratin, type II cytoskeletal 1 (KRT1), stabilizing the cytoskeletal integrity of podocytes. These ﬁndings identify a novel metabolic pathway linking glycolysis, serine metabolism, and podocyte injury with senescence, suggesting that targeting the PGK1-serine axis may offer therapeutic potential for slowing podocyte senescence and CKD progression. Podocytes are crucial components of the glomerular ﬁltration barrier, and their terminally differentiated nature makes them particularly vulnerable to injury. Podocyte injury is closely associated with the progression of chronic kidney disease (CKD), driven by various glomerular disorders, including hypertensive nephropathy (HN) and diabetic kidney disease (DKD)1,2. Podocyte injury triggers a cellular senescence program, resulting in a state of long-term non-proliferative cells, which ultimately leads to podocyte senescence3. Notably, podocyte senescence is a hallmark of glomerulosclerosis, as senescent podocytes contribute signiﬁcantly to the deterioration of the ﬁltration barrier, leading to proteinuria4. Since podocytes can not regenerate, the accumulation of senescent podocytes accelerates kidney function decline5. Previous studies have identiﬁed the renin-angiotensin system (RAS) activation, particularly angiotensin II (Ang II), as a critical factor in glomerular disease progression6. However, the direct contribution of Ang II to podocyte injury with senescence and the underlying mechanisms remains to be elucidated. Previous studies have demonstrated that Ang II impairs glycolytic ﬂux in podocytes, with subsequent energy deﬁciency exacerbating cellular damage. In particular, inhibition of the glycolytic enzyme 1Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China. 2Nephrology and Urology Research Institute of Wuhan University, Wuhan, China. 3These authors contributed equally: Hongtu Hu, Zijing Zhu, Lanlan Li, Jijia Hu. [e-mail:](e-mail: dr.liangwei@whu.edu.cn)[ dr.liangwei@whu.edu.cn](e-mail: dr.liangwei@whu.edu.cn); [chenzhaowei@whu.edu.cn](chenzhaowei@whu.edu.cn); [ghxding@whu.edu.cn](ghxding@whu.edu.cn) pyruvate kinase M2 (PKM2) has been shown to further disrupts podocyte function7–9.While the partial restoration of glycolytic ﬂux through PKM2 activation alleviates podocyte injury, a complete reversal of Ang II-induced podocyte injury remains unachieved, suggesting that additional metabolic pathways contribute to disease progression10. Recent st

FAQs

What is the main pathway connecting glycolysis-derived serine metabolism to podocyte injury with senescence?

The study identifies an Ang II–FOXA1–PGK1 axis that reduces L-serine biosynthesis, leading to mitochondrial dysfunction and increased cellular senescence in podocytes.

How does Angiotensin II affect PGK1 and L-serine metabolism in podocytes?

Ang II downregulates PGK1 expression through FOXA1, resulting in reduced L-serine production and downstream pathological changes in podocytes.

What experimental interventions alleviate podocyte injury and senescence in the CKD models?

Supplementing with L-serine or enhancing PGK1 expression restores mitochondrial function and reduces senescence-associated phenotypes in CKD mouse models.

Sep 30, 2026

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