Unraveling the Genetic Links Between Polycystic Kidney Disease and Hypertension Through ARL13B

Juan Chen,1,* Lei Song,2,* Shuqin Mei,1,* Jing Huang,3 Lili Fu,1 Chenchen Zhou,1 Xiaohua Hu,1 Liming Zhang,1 Cheng Xue,1,3 Zhiguo Mao1 1Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, People’s Republic of China; 2Division of Nephrology, People’s Hospital of Yangzhong City, Yangzhong, Jiangsu Province, People’s Republic of China; 3Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, USA*These authors contributed equally to this workCorrespondence: Zhiguo Mao; Cheng Xue, Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Fax +86-21-81885411, Email [email protected]; [email protected], [email protected]: Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is frequently accompanied by hypertension, with each condition potentially exacerbating the other. This study employs a bidirectional Mendelian randomization (MR) design to investigate the causal relationship between PKD and hypertension, alongside bioinformatics analyses to explore underlying genetic mechanisms.Methods: Genetic data for PKD and hypertension were obtained from the International Epidemiology Unit (IEU) Genome-Wide Association Study (GWAS) database. A bidirectional MR analysis was performed using nucleotide polymorphisms (SNPs) strongly associated with PKD and hypertension. Genetic annotation and enrichment analysis of SNPs were conducted using the Functional Mapping and Annotation (FUMA) platforms. Gene expression differences between PKD and controls were studied using the GEO database and single-cell data analysis tools. Quantitative PCR analysis of ARL13B mRNA levels in normal renal tubular epithelial cells (RCTEC), renal cystic epithelial cells (WT9-12), and ADPKD kidney tissues.Results: MR analysis demonstrated a causal effect of PKD on hypertension (IVW: P=0.038; OR=1.011; 95% CI: 1.001– 1.021) and a reverse causal effect of hypertension on PKD (IVW: P=0.042; OR=1.195; 95% CI: 1.007– 1.420). No significant heterogeneity or pleiotropy was detected. Genetic annotation identified 27 PKD genes closely associated with hypertension. Among them, functional enrichment analysis indicated ARL13B was involved in cilia morphology and dysfunction. Notably, RT-PCR results showed that ARL13B mRNA expression was significantly elevated in human ADPKD kidneys (P< 0.001) and WT9-12 cells (P< 0.05).Conclusion: Our bidirectional MR study demonstrated a causal effect of PKD on hypertension and a reverse influence of hypertension on PKD progression. Elevated ARL13B expression in ADPKD suggested a possible involvement of cilia-related pathways in the development of renal hypertension.Keywords: Mendelian randomization, polycystic kidney disease, hypertension, ARL13B, cilia dysfunction