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(+) levels. Deficiency in PPDPF disrupted NAD(+) 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.