The effect of growth differentiation factor 11 on sepsis-associated acute kidney injury
Patients with sepsis often experience severe renal dysfunction and damage and accelerate to end-stage renal failure with high mortality, which currently lacks effective therapeutic approaches. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-ß (TGF-ß) superfamily, has been proven to have therapeutic properties for a variety of acute and chronic inflammatory diseases. However, the role of GDF11 in sepsis-associated acute kidney injury (SAKI) remains elusive. Here, we aimed to investigate the role of GDF11 in SAKI and identify the signaling pathways modulated by GDF11. In a mouse model of cecal ligation and puncture (CLP)-induced SAKI, GDF11 was found to be highly expressed in tubular epithelial cells and macrophages in the kidney. 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 recombinant GDF11 (rGDF11) significantly mitigated these adverse effects. Further investigation revealed that GDF11 activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidative pathways, mainly through induction of peroxisome proliferator-activated receptor-? coactivator (PGC)-1a expression, which, in turn, inhibited overactivated inflammation and coagulation both in vivo and in vitro. Additionally, these beneficial effects of GDF11 were largely diminished by AAV-mediated PGC-1a knockdown and depletion of Nrf2 in CLP-induced SAKI mice. Overall, these findings demonstrate that GDF11 represents a promising therapeutic approach for SAKI and reveal the important role of PGC-1a/Nrf2 signaling in GDF11-mediated renal protection during SAKI. Overall design: Renal mRNA profiles of 8-week old cecal ligation and puncture (CLP)-treated C57BL/6J wild type (WT) mice (CLP group) and CLP plus recombinant GDF11 (rGDF11)-treated C57BL/6J WT mice (CLP+GDF11 group) were generated by deep sequencing, in triplicate, using the Illumina NovaSeq 6000 platform. rGDF11 was dissolved in PBS and administered intraperitoneally to mice post-CLP at doses of 500µg/kg. Kidney tissues were collected 24 h after CLP surgery.