Human PRDM16 adenoviral particles

Acute kidney injury (AKI) is a major public health problem. Sepsis accounts for more than 50% of AKI cases in ICUs. PRD1-BF1-RIZ1 homeodomain protein 16 (PRDM16) can inhibit the progression of diabetic nephropathy (DKD). However, its exact role and regulatory mechanisms in sepsis-induced AKI remain unclear. Here, researcher show that lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) trigger PRDM16 expression in Boston University mouse proximal tubule (BUMPT) cells and mouse kidney, respectively. Mechanistically, PRDM16 associates with the promoter region of nuclear factor-erythroid 2-related factor-2 (NRF2) and enhances its expression, which subsequently enhances the expression of glutathione peroxidase 4 (GPX4). Notably, these observations were confirmed in human renal tubular epithelial (HK-2) cells. Furthermore, ablation of PRDM16 in the proximal tubules of mouse kidneys suppressed the expression of NRF2 and GPX4, leading to a decreased glutathione (GSH)/oxidized glutathione (GSSG) ratio, increased Fe2+ and reactive oxygen species (ROS) generation, exacerbated ferroptosis, and progression of AKI. In contrast, PRDM16 knock-in exhibited the opposite effect. Finally, adenovirus (ADV)-PRDM16 plasmid or poly(lactide-glycolic acid) (PLGA)-encapsulated formononetin not only attenuated sepsis-induced AKI, but also liver, heart, and lung damage. In conclusion, PRDM16 prevents sepsis-induced multi-organ damage, including AKI, by inhibiting ferroptosis through the NRF2/GPX4 axis or GPX4.

To investigate the effects of PRDM16 on various organs including the kidney, adenovirus (ADV)-PRDM16 plasmid was injected via tail vein three days before the CLP model, and control mice received saline followed by CLP 18 h later. H&E staining of tissue sections showed that PRDM16 overexpression significantly ameliorated CLP-induced renal tubules (Figure 1A), alveoli (Figure 1B), myocardium (Figure 1C), and liver (Figure 1D) damage. Immunoblot analysis showed that PRDM16 overexpression significantly increased the protein levels of PRDM16, NRF2, and GPX4 in kidney, lung, heart, and liver tissues after sham surgery and CLP, but significantly decreased the protein levels of COX2 and NOX1. In conclusion, PRDM16 overexpression alleviates sepsis-induced multi-organ damage by upregulating the NRF2/GPX4 axis.

Figure 1. ADV-PRDM16 plasmid alleviates sepsis-induced multi-organ damage in mice through the NRF2/GPX4 axis. (Zheng Q, et al., 2024)