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

The articles by Li et al.1 and Melica et al.2 published in JASN have illuminated the role of the mechanosensitive Piezo1 cation channel in kidney pathophysiology. Li et al. demonstrated that Piezo1 activation promotes glomerulosclerosis in diabetic kidney disease and that inhibition of Piezo1 mitigates mechanical force–induced podocyte injury. Additional evidence suggests that Piezo1 contributes to kidney fibrosis and drives profibrotic changes in proximal tubular cells.3 Collectively, these and other studies—including ones in lupus nephritis and hypertensive kidney disease—support a contributory role of Piezo1 in CKD progression. Although mechanical stress is the sole known physiologic Piezo1 activator, four synthetic compounds—Yoda1, Yoda2, Jedi1, and Jedi2—have been identified as chemical Piezo1 activators. These compounds increase in a dose-dependent manner the open probability of Piezo1 without mechanical stimulation. Notably, Jedi1 and Jedi2 share structural similarities with 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a highly (>95%) protein-bound uremic retention solute that is normally excreted by the kidneys (Figure 1, top panel). Blood levels of CMPF are higher with declining kidney function by more than ten-fold.Figure 1: Proposed vicious cycle linking CMPF-mediated Piezo1 activation to kidney disease progression. Top panel: Jedi1 and Jedi2 are chemical activators of Piezo1. CMPF is hypothesized to activate Piezo1 such as Jedi1 and Jedi2 due to their shared 3-carboxylic acid methyl furan moiety (depicted in bold), the putative Piezo1-activating domain.4 Middle panel: AlphaFold3-modeled L15–L16 and L19–L20 extracellular loops (gray) with CMPF (carbon, cyan), Jedi1 (carbon, pink), and Jedi2 (carbon, green) in their optimal docking poses. Based on the affinity scores, we found that L19–L20 has the greatest potential for agonism, with a significant salt-bridge interaction predicted with the nearby arginine-920. Heteroatoms sulfur, oxygen, and nitrogen are shown in yellow, blue, and red. Bottom panel: progression of kidney disease leads to elevated blood concentrations of CMPF. Activation of Piezo1 by CMPF would trigger profibrotic signaling pathways3 and increase the vulnerability of podocytes to mechanical stress,1 further accelerating CKD progression. CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropionate.Given the structural resemblance between CMPF and Jedi1 and Jedi2, we hypothesized that CMPF might activate Piezo1 over an extended period and, in doing so, trigger a host of Ca2+-dependent pathways. Although definitive experimental validation is still pending, two lines of evidence suggest that CMPF docks on Piezo1. First, our group experimentally demonstrated that CMPF increases erythrocyte osmotic fragility similarly to Jedi1.4 Importantly, the greater osmotic fragility induced by both Jedi1 and CMPF is inhibited by the Piezo1 inhibitor GsMTx-4.4 Through this mechanism, CMPF may induce premature erythrocyte death and shorten red blood cell life span in CKD. Second, docking simulations (Figure 1, middle panel) show that CMPF has a similar predicted affinity (in kcal mol−1) as Jedi1 and Jedi2 at the relevant Piezo1 extracellular loops (L15–L16: Jedi1, −4.82; Jedi2, −4.50; CMPF, −5.10; L19–L20: Jedi1, −7.72; Jedi1, −7.24; CMPF, −7.21). An activation of Piezo1 by CMPF would point to a potentially self-reinforcing pathologic cycle in which CMPF-induced activation of Piezo1 accelerates kidney disease progression, thereby leading to further increases in CMPF blood concentrations and ongoing Piezo1 activation (Figure 1, bottom panel). The models established by Li et al.1 and Melica et al.2 provide opportunities to test our hypothesis. Incubation of mechanically stressed and unstressed podocytes and tubular cells with CMPF should induce Ca2+ influx, which can be assessed, e.g., by patch-clamp electrophysiology—a robust and direct method to examine the effects of CMPF on Piezo1 properties.