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Published on: November 10, 2021
Growth differentiation factor 11 attenuates sepsis-associated acute kidney injury by reducing inflammation and
Hong-Wei Wang1,2, Min-Min Wu1,2, Mian-Mian Zhu3
1Zhejiang Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Background:
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.
Purpose:
This study sought to explore GDF11's role in SAKI and determine the signaling pathways it modulates.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Growth differentiation factor 11 (GDF11) protects against sepsis-associated acute kidney injury (SAKI) by activating the PGC-1α/Nrf2 pathway. Supplementation with GDF11 mitigates kidney damage, inflammation, and apoptosis in SAKI models.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Sepsis frequently causes severe kidney damage and failure, with limited treatment options.
- Growth differentiation factor 11 (GDF11), a TGF-β superfamily member, shows therapeutic promise but its role in sepsis-associated acute kidney injury (SAKI) is unknown.
Purpose of the Study:
- Investigate the role of GDF11 in SAKI.
- Elucidate the signaling pathways modulated by GDF11 in SAKI.
Main Methods:
- Analyzed GDF11 expression in SAKI mouse kidneys.
- Assessed GDF11 knockdown and recombinant GDF11 (rGDF11) effects in a mouse SAKI model (cecal ligation and puncture - CLP).
- Utilized RNA sequencing, Western blot, RT-qPCR, and kit assays to explore mechanisms.
Main Results:
- GDF11 expression was elevated in tubular epithelial cells and macrophages in SAKI kidneys.
- GDF11 knockdown worsened renal dysfunction, tubular damage, and apoptosis in CLP-induced SAKI mice.
- rGDF11 supplementation significantly ameliorated SAKI.
- GDF11 activated Nrf2-regulated antioxidative pathways via PGC-1α induction, reducing inflammation and coagulation.
- GDF11's protective effects were dependent on PGC-1α and Nrf2.
Conclusions:
- GDF11 demonstrates therapeutic potential for SAKI.
- The PGC-1α/Nrf2 signaling pathway is critical for GDF11-mediated renal protection in SAKI.
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