Authors' Reply: A Self-Reinforcing Pathway Linking PIEZO1 and 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropionate, a Renal Retention Solute, with CKD Progression

We thank Kotango et al.1 for drawing attention to the role of Piezo1 in kidney pathophysiology and for advancing the thought-provoking idea that the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropanoic (CMPF) acid may activate Piezo1 in vivo. CMPF, a metabolite of both dietary and endogenous origin, accumulates in kidney failure. Its chemical similarity to the synthetic Piezo1 agonists, Jedi1 and Jedi2, suggests it could contribute to a self-sustaining cycle of kidney injury. The possibility that CMPF may act as a physiologic modulator of Piezo1 in normal conditions, but become maladaptive when chronically elevated in kidney disease, is compelling. Evidence on the contribution of Piezo1 to kidney pathophysiology has been recently presented,2–4 highlighting its complex and multidimensional role. Indeed, both its expression level and activity, as well as the severity of tissue damage, can tip the balance toward either protective or harmful outcomes. This complexity is likely linked to the intracellular message generated by Piezo1 as a mechanosensitive channel, namely, Ca2+ influx. Calcium is a remarkably versatile second messenger, and subtle differences in the kinetics, amplitude, and spatio-temporal organization of its signals can translate into profoundly different cellular fates. Interestingly, while CMPF-induced Piezo1 activation could be detrimental, our data,2 published in JASN, indicate that complete Piezo1 deletion exacerbate injury, reflecting the context-dependent role of Piezo1. One possible explanation is that CMPF may not act exclusively through Piezo1: It has been reported to impair mitochondrial function and energy metabolism, increase oxidative and endoplasmic reticulum stress, and interact with organic anion transporter–mediated pathways.5 In tubular cells, which rely heavily on fatty acid oxidation and are particularly vulnerable to metabolic stress, these actions could independently contribute to CKD progression, either in parallel with or downstream of Piezo1 activation. Future work should clarify whether CMPF acts in a threshold-dependent manner, whether it recruits Ca2+-dependent pathways distinct from those engaged by mechanical stress, and whether it prolongs Piezo1 channel opening to promote cytoskeletal remodeling and apoptosis. Direct experimental approaches in podocytes and tubular cells will be key to addressing these questions. In summary, the idea that CMPF may function as an endogenous Piezo1 agonist is intriguing and highlights how metabolic state and uremic toxins intersect with mechanosensitive pathways. Determining whether CMPF is a physiologic modulator that becomes maladaptive in CKD or a true pathogenic driver will be essential to define the translational relevance of CMPF–Piezo1 interaction—as a biomarker, a therapeutic target, or both.