Nephron-specific Panenxin-1 knockout alters sodium handling in the kidney

Background: Pannexin-1 (Panx1), a non-selective ion and solute permeable channel, was previously reported to involve in various mechanisms such as vasoconstriction, cell death and immune response. The protein forms a large pore ion channel, residing in the plasma membrane and capable of releasing ATP, which makes it an important part of purinergic signaling. Some aspects of sodium balance regulation in the kidney by purinergic signaling was studied before, for instance, ATP limits sodium reabsorption in the distal nephron in response to high dietary salt consumption, yet the source of ATP in nephron, initiator of purinergic signaling cascade, remains unclear. Hypothesis: Based on our previous research and reported purinergic regulation of sodium transporters, we hypothesize that Panx1 activity inhibits sodium reabsorption in the nephron through ATP release. Methods: To isolate role of Panx-1 in the kidney, we utilized a nephron-specific Pax8-driven Panx1 knockout mice under normal (0.4%) and high salt (4%) dietary conditions. Measurement of urine electrolytes and blood pressure evaluation with chronic telemetry recordings was performed. 3 days of 8 hours of inactive period recordings of blood pressure were compared at each week point. GFR measurement was performed by measuring FITC-Inulin clearance. Analysis of expression of sodium transporters was done by western blot and Epithelial sodium channel (ENaC) activity was assessed by patch clamp in the isolated collecting ducts of the kidney. Unpaired T test was performed for most statistical analyzes (* p< 0.05). Results: Knockout evaluation was performed by western blot, where Panx1 protein expression was significantly lower, compared to WT (Δ-0.47±0.1, *), and PCR of genomic DNA also confirmed recombination of target region in the kidney. We did not observe any difference in electrolyte secretion, urine output, sodium transporters expression and GFR between KO and WT under normal salt conditions. Under high salt conditions, Panx1 KO mice showed decreased sodium and chloride secretion after 1 day of challenge, compared to WT (2027.3±146 vs 2441.4±133.8 and 1639.6±173.7 vs 2040 ±106.3 µmol/day respectively, *) with no difference in urine potassium, osmolarity and output. On tissue level, we observed increase in β-ENaC abundance (Δ 0.70.5±0.2, *) and decreased total NKCC2 (Δ-0.53±0.2, *) at 5 weeks timepoint with no difference in expression of α, γ ENaC and NCC. We also observed increased ENaC activity in isolated tubules of Panx1 KO mice (NPo 1.19±0.13 vs 0.72±0.08 *; Po 0.68±0.05 vs 0.53±0.05 *), with no effect on number of channels (1.53±0.18 vs 1.73±0.28). Finally, we observed increase in mean blood pressure in male KO mice at 3 and 4 weeks timepoints compared to baseline (99.7±1.4 and 98.9± 1.2 vs 90.8±2.8 mmHg, *). Conclusion: Renal tubular Pannexin-1 regulates sodium reabsorption in the collecting duct through ENaC, presumably due to ATP release and contributes to blood pressure regulation in response to salt consumption. Supported by: NIH DK123266 and DK131114. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.