Editorial on the Research Topic: "Molecular Mechanisms Underlying Polycystic Kidney Disease: From the Smallest Bricks to the Big Scenario". Provisionally Accepted

Annarita Di Mise^1* Michael J. Caplan² Giovanna Valenti¹

• ¹University of Bari Aldo Moro, Italy
• ²Yale University, United States

PKD progression can be exacerbated by the presence of renal innate immune cells [11]. This interesting aspect is examined in the review by Agborbesong et al., focusing on epigenetic regulation, inflammation, and cell death as molecular mechanisms underlying ADPKD. It draws attention to the intricate interplay that drives cyst formation and disease progression, involving PKD gene alterations, epigenetic changes, inflammatory responses, and different forms of cell death. The inflammasome system responds to stimuli such as cellular damage by activating Caspase-1, and producing essential mediators of the inflammatory pathway, including IL-1β and IL-18 [11]. In the original research article by Swenson-Fields et al., the authors demonstrate that Caspase-1 knockout markedly reduced the onset of PKD in female mice, indicating sex-specific immunological responses, showing for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Currently, there is no cure for PKD other than renal transplantation [12]. Tolvaptan is the only drug approved by FDA proven to slow eGFR decline in ADPKD patients at the risk of rapid disease progression. Widespread use of tolvaptan is limited by the substantial aquaretic effects that it produces and by the potential for liver toxicity [13]. Recent advances in understanding the pathophysiology of PKD have led to new approaches to treatment via targeting different signaling pathways [13]. The original research article by Hallows et al. investigates the potential therapeutic effects of bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor. The authors demonstrate that BA inhibited cyst growth and improved mitochondrial function in vitro, and reduced disease severity in vivo, suggesting BA as a promising therapy for PKD, having beneficial effects alone and associated with tolvaptan. The review article by Zhou & Torres explores the emerging therapies for ADPKD with a focus on cAMP signaling. It discusses the role of cAMP and PKA signaling in ADPKD pathogenesis and the potential of targeting downstream pathways beyond cAMP production for therapeutic interventions. Over the past years, several in vitro and animal studies have shown that metabolic reprogramming might be a general feature of PKD [14]. Glucose metabolism is defective in ADPKD, with cystic cells reprogrammed to favor aerobic glycolysis. In addition to glucose, altered amino acid metabolism, reduced fatty acid oxidation, and dysregulated lipid metabolism have also been identified as key features of PKD [14]. In the mini-review by Bacaj & Pokai, the authors discuss metabolism-based approaches for ADPKD treatment, highlighting the role of metabolic reprogramming in cyst growth, specifically upregulated mTOR and c-Myc pathways, and the potential for targeting these pathways as therapeutic approaches. Obesity and overweight are very common in ADPKD patients and represent independent risk factors for the disease advancement. In this regard, Iliuta et al. examine the shared pathobiology between ADPKD and obesity, emphasizing the role of reduced AMPK activity and increased mTOR signaling. The pharmacological activation of AMPK is discussed as a promising approach to treat both ADPKD and obesity-related kidney disease. In conclusion, the present Research Topic provides an overview of the ongoing efforts to unravel the complex interaction of molecular signaling pathways associated with PKD progression, exploring innovative therapeutic approaches to improve patient outcomes.