PPDPF preserves integrity of proximal tubule by modulating NMNAT activity in chronic kidney diseases
Genome-wide association studies (GWAS) have identified loci associated with kidney diseases, but the causal variants, genes, and pathways involved remain elusive. Here, we identified a kidney disease gene called pancreatic progenitor cell differentiation and proliferation factor (PPDPF) through integrating GWAS on kidney function and multiomic analysis. PPDPF was predominantly expressed in healthy proximal tubules of human and mouse kidneys via single-cell analysis. Further investigations revealed that PPDPF functioned as a thiol-disulfide oxidoreductase to maintain cellular NAD<sup>+</sup> levels. Deficiency in PPDPF disrupted NAD<sup>+</sup> and mitochondrial homeostasis by impairing the activities of nicotinamide mononucleotide adenylyl transferases (NMNATs), thereby compromising the function of proximal tubules during injuries. Consequently, knockout of PPDPF notably accelerated the progression of chronic kidney disease (CKD) in mouse models induced by aging, chemical exposure, and obstruction. These findings strongly support targeting PPDPF as a potential therapy for kidney fibrosis, offering possibilities for future CKD interventions.
Authors
- Qihui Wu (ORCID: https://orcid.org/0000-0001-5979-8297)
- Yu Liu (ORCID: https://orcid.org/0000-0002-1844-9303)
- Jing Nie (ORCID: https://orcid.org/0000-0003-1002-5562)
- Yuting Guan (ORCID: https://orcid.org/0000-0003-1866-270X)
- Wubin Ding (ORCID: https://orcid.org/0000-0002-5355-7561)
- Xiaohui Yao (ORCID: https://orcid.org/0000-0002-8530-7989)
- D. Zhang (ORCID: https://orcid.org/0009-0006-4623-0153)
- Dali Li (ORCID: https://orcid.org/0000-0002-0046-8493)
- Xiaofei Li (ORCID: https://orcid.org/0000-0002-9991-7534)
- Na Liu (ORCID: https://orcid.org/0000-0001-5806-8209)
- Kaiyuan Wang (ORCID: https://orcid.org/0000-0001-9567-1410)
- Yuwei Wang (ORCID: https://orcid.org/0000-0001-8819-3844)
- Guofeng Xu (ORCID: https://orcid.org/0000-0002-5104-5386)
- Hongquan Geng (ORCID: https://orcid.org/0000-0003-4722-416X)
- Kai Lin (ORCID: https://orcid.org/0000-0003-4445-4939)
- Rui Zheng (ORCID: https://orcid.org/0000-0003-4446-8724)
- Qingxun Hu (ORCID: https://orcid.org/0000-0001-9288-6491)
- Yi Zhong (ORCID: https://orcid.org/0009-0009-1661-6110)
- Fubin Zhong (ORCID: https://orcid.org/0000-0003-1496-9050)
- Xiaoliang Fang
Institutions
- Shanghai University (CN)
- Chongqing Normal University (CN)
- Salk Institute for Biological Studies (US)
- Harbin Engineering University (CN)
- Peking University (CN)
- XinHua Hospital (CN)
- Karolinska Institutet (SE)
- Shanghai East Hospital (CN)
- Peking University First Hospital (CN)
- Children's Hospital of Fudan University (CN)
- Institute of Neurobiology (BG)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-19
- DOI
- https://doi.org/10.1126/sciadv.adr8648
- Citations
- 3
- Primary Topic
- Renal and related cancers
- Type
- article
- Field-Weighted Citation Impact
- 2.42