Growth Differentiation Factor 15 (GDF15) Protects Against Sepsis-Associated Acute Kidney Injury via Suppression of TLR4-MyD88-NF-κB Signaling and Ferroptosis.

Authors

Chengyi Yang, Le Zhao, Jia Di, Qiangyan Hu

Published in

BioFactors (Oxford, England). Volume 52. Issue 4. Pages e70138.

Abstract

Sepsis-associated acute kidney injury (SAKI) lacks mechanism-based therapies, with upstream ferroptosis regulators undefined. This study investigated growth differentiation factor 15 (GDF15) as a suppressor of TLR4-MyD88-NF-κB signaling and associated ferroptosis. Differential GDF15 expression was identified by integrated analysis of three GEO datasets (GSE232404, GSE30718, GSE44925) and validated in SAKI patient kidney tissue (n = 30 vs. controls n = 25) and in kidneys from cecal ligation and puncture (CLP) mice. CLP mice received recombinant GDF15 (rmGDF15) (50 ng/kg ip); renal function (Scr/BUN), histology, kidney injury molecule-1 (KIM-1), serum TNF-α/IL-1β/IL-6 (ELISA), and 7-day survival were assessed. Oxidative stress/ferroptosis was quantified by DCFH-DA ROS imaging and kits (MDA, GSH, SOD, NADPH, Fe, GPX4 activity); TLR4-MyD88-NF-κB by qRT-PCR, Western blot, and Immunohistochemistry. LPS (1 μg/mL, 48 h)-stimulated HK-2 cells underwent shGDF15 lentiviral knockdown (puromycin 2 μg/mL) ± TAK242 (1 μM); viability (CCK-8), apoptosis (Annexin V/PI flow), cytokines (ELISA/qRT-PCR), ROS, ferroptosis markers, and pathway activation were evaluated. GDF15 was upregulated in SAKI datasets, patient kidney tissue, and CLP kidneys. GDF15 supplementation improved survival, lowered Scr/BUN and KIM-1, attenuated tubular injury, and reduced systemic proinflammatory cytokines. It decreased renal ROS, MDA and Fe while restoring GSH, SOD, NADPH, GPX4 activity, and SLC7A11 expression, and suppressed TLR4-MyD88-NF-κB signaling. In HK-2 cells, GDF15 silencing aggravated LPS-induced loss of viability, apoptosis, cytokine release, oxidative stress, and ferroptosis markers, all reversed by TAK242. In conclusion, GDF15 is a stress-inducible renoprotective factor that suppresses TLR4 signaling, ferroptosis markers, and inflammation in SAKI, suggesting exogenous administration as a promising therapeutic strategy.

PMID:
42552263
Bibliographic data and abstract were imported from PubMed on 05 Aug 2026.

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