Chronic kidney disease (CKD) has become a global health crisis, affecting approximately 15% of the world’s population and ranking as the ninth leading cause of death worldwide. Despite advancements in medical research, effective treatments to slow or reverse the progression of CKD remain limited. The search for novel therapeutic targets is critical, as kidney function can deteriorate progressively, leading to end-stage renal failure and the need for dialysis or kidney transplants. However, recent research spearheaded by the Children’s Hospital of Fudan University in China has uncovered a potential game-changer in the fight against CKD—a gene called pancreatic progenitor cell differentiation and proliferation factor (PPDPF). This discovery could not only deepen our understanding of kidney disease but also offer new avenues for treatment.
The Genetic Puzzle of Chronic Kidney Disease
Research into the genetic basis of CKD has revealed nearly 800 genetic loci linked to kidney function, thanks to extensive genome-wide association studies (GWAS). However, these genetic variants are predominantly located in noncoding regions of the genome, where their roles in regulating gene activity and disease mechanisms are not entirely clear. This gap in understanding has been one of the major hurdles in developing targeted treatments for CKD. Despite these findings, the specific genes and molecular pathways involved in the early stages of kidney disease remain largely unknown.
In recent years, scientists have turned to multi-omic approaches, combining genomics, transcriptomics, and proteomics, to map out the molecular underpinnings of CKD. One such gene that emerged from this research is PPDPF. This gene had already shown strong associations with kidney function in large-scale population studies, prompting scientists to investigate its role in kidney health and disease. What they discovered in their groundbreaking study published in Science Advances could hold the key to protecting kidney cells and slowing the progression of chronic kidney damage.
PPDPF: A New Player in Kidney Function
PPDPF had previously been studied in other contexts, including its role in pancreatic cell differentiation and other physiological processes. However, its involvement in kidney disease had not been explored until this research team delved into its potential role in chronic kidney injury. Their study, titled “PPDPF Preserves Integrity of Proximal Tubule by Modulating NMNAT Activity in Chronic Kidney Diseases,” sought to understand how PPDPF could influence kidney cell function, particularly in the early stages of injury.
The researchers conducted an extensive analysis, utilizing a range of experimental methods including genome-wide association studies, single-cell and bulk RNA sequencing, and multi-omic data integration. The goal was to understand the earliest molecular events in kidney injury and how PPDPF could play a protective role during these early stages.
The Study: Exploring PPDPF in Animal and Human Models
The team analyzed kidney samples from both mouse models and human datasets to investigate the gene’s activity during early kidney injury. In the mouse experiments, the researchers used models that mimicked various forms of chronic kidney damage, including those induced by aging, chemical exposure, and urinary obstruction. They collected kidney samples at different time points—one day and five days after injury—to track the progression of gene expression changes.
In addition to mouse models, the study also included data from human kidney samples. These were drawn from a variety of sources, including individuals with acute kidney injury, preimplantation kidney donors, and single-cell sequencing datasets. This combination of mouse and human data provided a comprehensive picture of PPDPF’s role in kidney health across different species and conditions.
Using advanced genetic tools, the researchers created genetically modified mice lacking the PPDPF gene through CRISPR-Cas9 technology. They also exposed the mice to various forms of kidney injury to simulate chronic kidney disease and observed the effects of PPDPF loss on kidney function. Furthermore, the team used gene knockdown and overexpression techniques in cultured kidney cells, along with biochemical assays, to measure mitochondrial activity, NAD⁺ levels, and the protein interactions that are regulated by PPDPF.
PPDPF’s Impact on Kidney Cells
The results were striking. PPDPF was found to be highly expressed in healthy proximal tubule cells, which are essential for maintaining kidney function. In both mouse and human samples, PPDPF expression increased significantly during the early stages of kidney injury, suggesting that the gene plays a role in responding to damage.
When PPDPF expression was experimentally reduced in mouse models, the consequences were severe. The loss of PPDPF led to impaired mitochondrial function, a hallmark of kidney damage. Mitochondria, the energy-producing organelles within cells, play a crucial role in maintaining cellular health, particularly in energy-demanding organs like the kidneys. The loss of PPDPF resulted in a dramatic reduction in NAD⁺ (nicotinamide adenine dinucleotide) levels, an essential molecule for mitochondrial function and cellular metabolism. As a result, the kidneys in these PPDPF-deficient mice exhibited more severe damage and worsened disease outcomes in models of chronic kidney injury.
Interestingly, supplementation with NAD+—but not its metabolic precursor NMN (nicotinamide mononucleotide)—was able to mitigate some of the kidney damage in the PPDPF knockout mice. This finding suggests that PPDPF’s protective effects may be linked to its ability to regulate NAD+ homeostasis, a critical component of cellular energy metabolism.
The Mechanism: PPDPF and NMNAT Activity
Further investigation into PPDPF’s molecular function revealed that it modulates the activity of NMNAT (nicotinamide mononucleotide adenylyltransferase), an enzyme involved in NAD+ biosynthesis. Overexpression of PPDPF led to increased NMNAT activity, enhanced mitochondrial function, and elevated NAD+ levels in the kidneys. This, in turn, improved kidney cell survival and reduced signs of fibrosis and injury in renal tissue. These findings suggest that PPDPF plays a key role in regulating NAD+ metabolism, which is critical for maintaining kidney health, especially during periods of stress or injury.
Implications for Chronic Kidney Disease Treatment
The results of this study suggest that PPDPF is a central regulator of kidney function and plays a critical role in modulating the progression of chronic kidney disease. By preserving mitochondrial function and regulating NAD+ levels, PPDPF helps maintain the integrity of kidney cells, particularly in the proximal tubules, which are often the first cells to be affected during kidney injury.
Given the findings, PPDPF could be a promising therapeutic target for treating CKD, particularly in the early stages of the disease. Researchers have already identified potential strategies for targeting PPDPF, including gene therapy approaches or small molecules that can enhance its expression or mimic its activity. Such interventions could slow the progression of kidney fibrosis, reduce the severity of kidney damage, and improve patient outcomes.
Moreover, the study’s focus on NAD+ metabolism could open up new avenues for research into other diseases related to mitochondrial dysfunction and cellular energy deficits. NAD+ has already been implicated in a range of age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders. Targeting PPDPF or NAD+ metabolism could have broad implications for treating a variety of conditions beyond chronic kidney disease.
Conclusion: A New Frontier in Kidney Disease Research
The discovery of PPDPF’s role in protecting kidney cells and regulating NAD+ metabolism represents a major step forward in the understanding of chronic kidney disease. By identifying a specific gene that can modulate the early stages of kidney injury, this research offers new hope for developing targeted therapies that could slow the progression of CKD and improve quality of life for millions of patients worldwide.
As the global burden of kidney disease continues to rise, researchers are increasingly turning to molecular genetics and multi-omic approaches to uncover new therapeutic targets. PPDPF stands out as a promising candidate, with the potential to transform the way we treat kidney disease. With further research and clinical development, targeting PPDPF could one day become a cornerstone of chronic kidney disease therapy, offering a much-needed solution to one of the world’s most pressing health challenges.
References: Xiaoliang Fang et al, PPDPF preserves integrity of proximal tubule by modulating NMNAT activity in chronic kidney diseases, Science Advances (2025). DOI: 10.1126/sciadv.adr8648
Shin-ichiro Imai, PPDPF: Preventing kidney disease through NAD + regulation, Science Advances (2025). DOI: 10.1126/sciadv.adw6815