Gaps in PLTP mechanism research in sepsis-associated acute kidney injury and improvement strategies based on new evidence

Abstract

Dear editor,

We were highly intrigued by the study conducted by Jiang and colleagues, which illustrates the significant role of phospholipid transfer protein (PLTP) in sepsis-associated acute kidney injury (SA-AKI) [1]. The study on the role of PLTP in SA-AKI provides valuable insights into its potential as a therapeutic target. However, several critical gaps in the mechanistic understanding of PLTP's protective effects limit its translational potential. Here, we highlight these gaps and propose improvement strategies based on recent evidence.

The study suggests that PLTP exerts anti-inflammatory effects by neutralizing LPS and facilitating its clearance. However, the specific signaling pathways involved, such as TLR4/NF-κB, remain under-explored. Recent studies have shown that TLR4/NF-κB activation is a key driver of renal inflammation in sepsis [2]. Future research should investigate whether PLTP directly modulates this pathway by measuring downstream inflammatory markers and key proteins in renal tissues.

While the study observes improved mitochondrial structure in PLTP-treated mice, the molecular mechanisms underlying this protection are unclear. Mitochondrial dysfunction, characterized by impaired dynamics and increased oxidative stress, is a hallmark of SA-AKI. Recent work by Li et al. highlights the role of mitophagy in mitigating renal injury during sepsis [3]. Future studies should assess mitochondrial dynamics-related proteins and mitophagy markers to determine whether PLTP enhances mitochondrial quality control. Additionally, measuring reactive oxygen species (ROS) levels and antioxidant enzyme activity could clarify PLTP's role in reducing oxidative stress.

The study mentions PLTP's involvement in lipid transport but does not explore its impact on specific lipid mediators, such as sphingosine-1-phosphate (S1P). S1P, transported by HDL, has been shown to improve renal microcirculation and reduce inflammation through S1P1 receptor activation. Bajwa et al. reported that S1P1 receptor agonists attenuate ischemic kidney injury, suggesting a potential link between PLTP and S1P signaling [4]. Future research should measure S1P levels in plasma and renal tissues and evaluate S1P1 receptor expression to determine whether PLTP's protective effects are mediated through this pathway.

The study focuses on PLTP mRNA and protein expression but overlooks potential epigenetic and non-coding RNA regulation. Sepsis-induced epigenetic modifications, such as DNA methylation and histone acetylation, can significantly alter gene expression [5]. Additionally, miRNAs like miR-155 and miR-146a have been implicated in regulating inflammatory responses. Future studies should investigate whether PLTP expression is modulated by epigenetic changes or miRNAs, providing a more comprehensive understanding of its regulatory mechanisms.

In conclusion,while the study provides a foundational understanding of PLTP's role in SA-AKI, its mechanistic gaps hinder the development of targeted therapies. By integrating recent evidence on TLR4/NF-κB signaling, mitochondrial dynamics, S1P-mediated pathways, and epigenetic regulation, future research can bridge these gaps and advance PLTP's potential as a therapeutic target for SA-AKI.

No datasets were generated or analysed during the current study.

No datasets were generated or analyzed during the current study.

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None to declare.

This research was supported by Baoding Science and Technology Plan Self-finiancing Project (2441ZF205,2441ZF235,2441ZF236).

Authors and Affiliations

1. 2nd Department of Ophthalmology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China

   Dongrui Liang

2. Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding Great Wall North Street No 320, Baoding, 071000, Hebei, People’s Republic of China

   Xiaodong Li

Authors

1. Dongrui LiangView author publications

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2. Xiaodong LiView author publications

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Contributions

DL mainly wrote the manuscript text, XL made valuable suggestions, and DL and XL eventually revised the manuscript. All the authors reviewed the manuscript.

Corresponding author

Correspondence to Xiaodong Li.

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The authors confirmed that they have read and approved the final version of the manuscript. They further declared that the work described in the manuscript is original and has not been published elsewhere.

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The authors declare no competing interests.

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Liang, D., Li, X. Gaps in PLTP mechanism research in sepsis-associated acute kidney injury and improvement strategies based on new evidence. Crit Care 29, 83 (2025). https://doi.org/10.1186/s13054-025-05310-0

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• Received: 31 January 2025

• Accepted: 06 February 2025

• Published: 19 February 2025

• DOI: https://doi.org/10.1186/s13054-025-05310-0

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