A recent study by researchers at the Children’s Hospital of Fudan University, China, has identified pancreatic progenitor cell differentiation and proliferation factor (PPDPF) as a crucial regulator of kidney health. Published in Science Advances, the study reveals that PPDPF supports key enzymes that maintain cellular energy levels, highlighting its potential as a therapeutic target for chronic kidney disease (CKD).
PPDPF emerged as a candidate gene due to its strong genomic associations with kidney function in large-scale population studies. Variants linked to decreased kidney performance were correlated with PPDPF expression changes across multiple expression quantitative trait locus (eQTL) analyses, including bulk tissue, cell-type-specific, and meta-analyses. While PPDPF has been studied in other physiological and pathological contexts, its role in kidney disease had not been previously explored.
To investigate PPDPF’s role in kidney disease, researchers integrated genome-wide association studies (GWAS) and multi-omic analyses. They examined gene activity in mouse models and human datasets, including samples from acute kidney injury patients and preimplantation kidney donors. Bulk and single-cell RNA sequencing tracked gene expression changes post-injury, while CRISPR-Cas9 was used to generate PPDPF-deficient mice. Additional models were developed through chemical exposure, surgical obstruction, and aging. Functional studies, including gene knockdown, overexpression, and biochemical assays, assessed mitochondrial function, NAD⁺ metabolism, and PPDPF-related protein interactions.
The findings revealed that PPDPF is highly expressed in healthy proximal tubule cells and is upregulated during early kidney injury. PPDPF deficiency led to mitochondrial dysfunction, NAD⁺ depletion, and severe kidney damage across multiple CKD models. Notably, NAD⁺ supplementation, but not its precursor NMN, mitigated kidney injury in PPDPF-deficient mice. Conversely, PPDPF overexpression enhanced mitochondrial activity, increased NAD⁺ and NMNAT levels, and reduced fibrosis markers.
CKD affects approximately 15% of the global population and is the ninth leading cause of death worldwide. Despite its prevalence, effective treatments to slow disease progression remain limited. Although GWAS have linked nearly 800 genetic loci to kidney function, over 90% of these variants reside in noncoding regions, making it difficult to determine their functional significance. The molecular mechanisms underlying early-stage CKD remain largely unknown.
Beyond kidney disease, PPDPF plays essential roles in various physiological and pathological processes. It promotes lung adenocarcinoma by inhibiting apoptosis and immune cytotoxicity, while PPDPF knockout suppresses KRAS-driven pancreatic ductal adenocarcinoma. In non-tumor contexts, PPDPF prevents Raptor ubiquitination, reducing lipid synthesis and mitigating fatty liver disease. These findings position PPDPF as a critical regulator of NAD⁺ homeostasis and CKD progression, offering a promising therapeutic target for kidney fibrosis and CKD treatment.
References:
- Fang X, Zhong Y, Zheng R, Wu Q, Liu Y, Zhang D, et al. PPDPF preserves integrity of proximal tubule by modulating NMNAT activity in chronic kidney diseases. Science Advances. 2025 Mar 19;11(12):eadr8648.
- Imai S ichiro. PPDPF: Preventing kidney disease through NAD+ regulation. Science Advances. 2025 Mar 19;11(12):eadw6815.