New CKD Risk Gene Could Be a Future Treatment Target

TOPLINE:

Deficiency of the pancreatic progenitor cell differentiation and proliferation factor (PPDPF) gene is a risk factor for chronic kidney disease (CKD), a multiomic study revealed.

METHODOLOGY:

• Researchers analyzed the early-stage transcriptomes of CKD tissues.
• By integrating genome-wide association studies on kidney function and multiomic analysis, they identified the kidney disease gene PPDPF.
• They knocked out PPDPF in mice to observe the consequences for CKD.

TAKEAWAY:

• Researchers found that PPDPF, which helps maintain cellular metabolism in the proximal tubules in both mouse and human kidneys, was upregulated during the early stages of CKD.
• Mechanistic investigations showed that PPDPF deficiency resulted in mitochondrial dysregulation by inhibiting nicotinamide mononucleotide conversion into nicotinamide adenine dinucleotide (oxidized form, NAD+).
• Knocking out PPDPF aggravated aging-, cisplatin-, unilateral ureteral obstruction-, and folic acid-induced mouse CKD models, whereas supplementation with NAD+ alleviated renal dysfunction.
• Additional investigations showed that adenovirus-mediated overexpression of PPDPF protected against renal injuries in vivo.

IN PRACTICE:

“These findings strongly support targeting PPDPF as a potential therapy for kidney fibrosis, offering possibilities for future CKD interventions,” the authors wrote.

SOURCE:

This study was led by Xiaoliang Fang, Children’s Hospital of Fudan University, Shanghai, China, and published online in Science Advances. A related Focus article by Shin-ichiro Imai, Washington University School of Medicine, St. Louis, Missouri, provides additional context.

LIMITATIONS:

This study was preclinical, based on analyses of early-stage transcriptomes of CKD tissues.

DISCLOSURES:

This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Shanghai Rising-Star Program, the Natural Science Foundation of Chongqing, China, the Ningxia Hui Autonomous Region Key Research and Development Project, Shanghai Fourth People’s Hospital affiliated to Tongji University School of Medicine, the Fundamental Research Funds for the Central Universities, Science and Technology Commission of Shanghai Municipality grants, the Fundamental Research Funds for the Central Universities at Harbin Engineering University, and the Shandong Provincial Natural Science Foundation. The authors declared no competing interests.