PPDPF-mediated NAD+ homeostasis is required for proximal tubule maintenance in chronic kidney disease

Renal fibrosis is the common pathological hallmark of chronic kidney disease (CKD) progression. However, effective targets are still limited. Using single-cell RNA-seq analysis, we discovered that PPDPF was predominantly expressed in a healthy subcluster of proximal tubule during the early stages of renal fibrosis. Further investigations revealed that PPDPF functioned as thiol-disulfide oxidoreductase to maintain cellular NAD+ levels. Deficiency in PPDPF disrupted NAD+ and mitochondrial homeostasis by impairing mononucleotide adenylyl transferases (NMNAT) activities, thus compromising the function of healthy proximal tubules during injuries. Consequently, knockout of PPDPF significantly accelerated the progression of CKD in mouse models induced by aging, chemical exposure and obstruction. Finally, kidney functional GWAS analysis identified PPDPF as a top target gene, and it was highly expressed in healthy proximal tubules of human kidney samples. Therefore, these findings provide compelling evidence supporting the potential therapeutic efficacy of targeting PPDPF for the treatment of renal fibrosis.