Integrated Single‐Cell Transcriptome and eQTL Analyses Reveal the Role of PZP in Aging and Chronic Kidney Disease

ABSTRACT Background Aging is a known driver of chronic kidney disease (CKD), yet the genetic mechanisms linking these two conditions remain unclear. This study aims to explore the role of CD8+ central memory T (T CM ) cells and their associated gene expression in the interaction between aging and CKD. Methods Peripheral blood samples from young controls, elderly individuals, and CKD patients were analyzed using single‐cell RNA sequencing to investigate immune cell populations. Expression quantitative trait loci (eQTL) and Mendelian randomization analyses were performed using data from genomic cohorts, including the UK Biobank and FinnGen, to assess causal relationships. Experimental validation evaluated correlations between pregnancy zone protein (PZP) expression and clinical indicators such as age, glomerular filtration rate (GFR), serum creatinine, and proteinuria. Results Increased proportions of CD8+ T CM cells were observed in elderly individuals and CKD patients. PZP was identified as a key genetic factor in CKD progression and aging, linked to metabolic reprogramming and impaired intercellular communication. PZP expression correlated significantly with aging ( r = 0.818, p = 0.047), reduced GFR ( r = −0.557, p = 0.011), elevated serum creatinine ( r = 0.507, p = 0.019), and proteinuria ( r = 0.761, p = 0.047). Conclusions Shared genetic and immunological mechanisms link CKD and aging, with CD8+ T CM cells contributing to immune dysregulation and chronic inflammation. The dual role of PZP, involving its upregulation, disrupted immune communication, and metabolic reprogramming, highlights its potential as a biomarker and therapeutic target for aging‐associated kidney diseases.