Protective gene found to preserve mitochondria during kidney disease progression microbiologystudy

Research led by Children’s Hospital of Fudan University in China has found that a gene called pancreatic progenitor cell differentiation and proliferation factor (PPDPF) helps protect kidney cells by supporting enzymes involved in maintaining cellular energy levels during chronic kidney disease.

Chronic kidney disease affects approximately 15% of the global population and is currently the ninth leading cause of death worldwide. Treatments that can slow the progression of this condition remain limited.

Genome-wide association studies have identified nearly 800 genetic loci associated with kidney function, yet more than 90% of these variants are located in noncoding regions. Specific genes and molecular mechanisms involved in early-stage chronic kidney disease remain incompletely understood.

PPDPF was selected for investigation after showing strong genomic associations with kidney function in large-scale population studies.

Variants linked to decreased kidney performance were also associated with changes in PPDPF expression across multiple types of expression quantitative trait locus (eQTL) analysis, including bulk tissue, cell-type specific, and meta-analyses. Although the gene has been studied in other physiological and pathological contexts, its role in kidney disease had not been experimentally tested.

In the study, “PPDPF preserves integrity of proximal tubule by modulating NMNAT activity in chronic kidney diseases,” published in Science Advances, researchers integrated genome-wide association studies on kidney function and multi-omic analysis with the goal of understanding kidney fibrogenesis from the earliest cellular events.

Kidney samples were collected from both mouse models and previously published human datasets to examine gene activity during early-stage injury.

In the mouse experiments, researchers analyzed three control kidneys, three collected one day after obstruction-induced injury, and two collected five days after injury. Human data included samples from individuals with acute kidney injury and preimplantation kidney donors, drawn from single-cell and bulk RNA sequencing datasets.

Bulk and single-cell RNA sequencing were performed on mouse kidneys following induced injury to track gene expression over time. Genetically modified mice lacking PPDPF were developed using CRISPR-Cas9, and additional models were created through chemical exposure, surgical obstruction, and aging.

Human kidney data were analyzed from existing single-cell sequencing datasets and gene expression databases. Researchers used gene knockdown and overexpression in kidney cells, along with biochemical assays to measure mitochondrial activity, NAD⁺ levels, and protein interactions related to PPDPF function.

PPDPF was found to be strongly expressed in healthy proximal tubule cells and increased during the early stages of kidney injury in both mouse models and human samples.

Experimental loss of PPDPF impaired mitochondrial structure and function, leading to reduced NAD⁺ levels. Mice lacking PPDPF (knockout) developed more severe kidney damage in multiple models of chronic kidney disease, including those caused by aging, chemical injury, and urinary obstruction.

Supplementation with NAD⁺, but not with its metabolic precursor NMN, reduced signs of kidney injury in these mice. Overexpression of PPDPF improved mitochondrial activity, increased NAD⁺ levels, enhanced NMNAT activity, and reduced markers of fibrosis and injury in renal tissue.

According to the authors, the findings suggest that “PPDPF is a regulator of NAD⁺ homeostasis involved in modulating CKD progression,” which strongly supports targeting PPDPF as a potential therapy for kidney fibrosis with possibilities for future chronic kidney disease interventions.

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