Weighted co-expression reveals early circadian and metabolic dysregulation in precystic kidneys

Autosomal dominant polycystic kidney disease (ADPKD) initiates long before cysts appear, yet the molecular triggers of this precystic phase remain poorly defined. To gain more insight into these early alterations, we applied cross-species Weighted Gene Coexpression Network Analysis (WGCNA) to renal transcriptomes from inducible Pkd1 -knockout (iKsp- Pkd1 del ) mice across precystic and cystic stages. Instead of constructing a new network, expression profiles were projected onto three hundred and forty-seven curated rat kidney co-expression modules from the TXG-MAPr framework, enabling direct systems-level comparison with conserved injury signatures. Forty-two transcriptionally active modules emerged, including twenty-one already deregulated during the morphologically normal precystic phase. Early upregulated modules showed activation of circadian regulators ( Bmal1/Arntl , Per1 , Per3 , Npas2 ) and sterol biosynthesis under Srebf2 control, whereas mitochondrial and oxidative-phosphorylation modules were markedly repressed. Transcription-factor enrichment revealed distinct regulatory axes: circadian control by BMAL1, metabolic regulation through SREBP2 (encoded by Srebf2 ), and inflammatory/cytokine signaling mediated by STAT3, p53, and NF-κB. These regulatory programs diverged transcriptionally within two weeks of Pkd1 loss, establishing an epithelial-driven phase characterized by circadian misalignment, metabolic rewiring, mitochondrial suppression and concomitant low-level inflammatory signaling. Inflammatory and stress-response modules intensified during later cystic stages. Notably, Pkd2 clustered within a small but transcriptionally active high-ranked module suggesting early perturbation of the polycystin complex. Together, these data define precystic ADPKD as a convergence of independent epithelial programs accompanied by early inflammatory engagement that precedes overt cyst expansion, providing a modular framework for early biomarker discovery and therapeutic targeting.