What type of study is this?

This is a RNA sequencing study (also classified as: Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), kit assays, Animal Study).

September 5, 2025Open Access

Growth differentiation factor 11 attenuates sepsis-associated acute kidney injury by reducing inflammation and coagulation via PGC-1α/Nrf2 activation

Key Points

GDF11 replenishment significantly mitigates renal dysfunction in sepsis-associated acute kidney injury mice, enhancing survival.
RNA sequencing and various assays demonstrated that GDF11 activates PGC-1α/Nrf2 pathways, reducing inflammation and cellular damage.
Gene silencing of GDF11 led to increased renal apoptosis and damage in mice, emphasizing its protective role in kidney health.
The findings suggest targeting GDF11 could be a novel therapeutic option for treating sepsis-associated renal injury.

Abstract

Patients with sepsis commonly endure severe renal dysfunction and damage, hastening to end-stage renal failure with high mortality, and effective treatment options are currently lacking. Growth differentiation factor 11 (GDF11), belonging to the transforming growth factor beta (TGF-β) superfamily, has shown therapeutic potential for numerous acute and chronic inflammatory conditions. Nevertheless, its function in sepsis-associated acute kidney injury (SAKI) remains unclear. This study sought to explore GDF11's role in SAKI and determine the signaling pathways it modulates. Alterations in GDF11 expression in the kidneys of mice with SAKI were analyzed. The influence of GDF11 knockdown and recombinant GDF11 (rGDF11) supplementation on cecal ligation and puncture (CLP)-induced SAKI in mice was determined. RNA sequencing, Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and kit assays were performed to explore the underlying mechanisms. Tubular epithelial cells and macrophages in the kidneys of CLP-induced SAKI mice exhibited high levels of GDF11 expression. Moreover, gene silencing of GDF11 using adeno-associated virus (AAV) aggravated renal dysfunction, increased tubular damage, and augmented renal apoptosis in CLP-induced SAKI mice. In contrast, replenishment of rGDF11 significantly mitigated these adverse effects. Further studies indicated that GDF11 stimulated the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidative pathways, primarily by inducing the expression of Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which subsequently decreased excessive inflammation and coagulation. Additionally, these beneficial effects of GDF11 were largely diminished by AAV-mediated PGC-1α knockdown and depletion of Nrf2 in CLP-induced SAKI mice. In summary, these findings indicate that GDF11 is a potential therapeutic approach for SAKI and highlight the crucial role of PGC-1α/Nrf2 signaling in GDF11-mediated renal protection during SAKI.

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