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Extracellular ATP (eATP) can act as a mediator of TEC\u2013macrophage crosstalk. However, whether and how eATP functions in Aldo-induced renal injury remain unknown. A deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mouse model and a primary mouse renal tubular epithelial cell (mTEC)\u2013bone marrow-derived macrophage (BMDM) coculture model were developed. To investigate the relationship between Aldo\/MR and eATP signaling in TEC\u2013macrophage crosstalk, specific inhibitors, adeno-associated virus (AAV)-shRNA and small interfering RNA (siRNA) were used. scRNA-seq analysis of kidneys from DOCA-salt mice was performed for verification. Urinary ATP levels and renal pannexin1 (PANX1, an ATP efflux channel) expression increased significantly in DOCA-salt mice, whereas the selective mineralocorticoid receptor (MR) antagonist finerenone treatment reduced urinary ATP levels, PANX1 expression, tubular injury, and macrophage-related inflammation. Inhibiting PANX1-eATP-P2X7 signaling with the PANX1 inhibitor probenecid, specifically knocking down tubular PANX1, or using the eATP ectonucleotidase apyrase or the P2X7 blocker AZ10606120 mitigated renal tubular damage and NLRP3-mediated pyroptosis in the renal cortex of DOCA-salt mice. Similarly, in mTECs, finerenone suppressed Aldo-induced ATP release and PANX1 upregulation. A luciferase assay confirmed the binding site of MR to the PANX1 transcription promoter. Coculture of BMDMs with mTECs under Aldo stimulation significantly increased NLRP3-mediated BMDM pyroptosis and migration. However, these effects were reversed by treating the mTECs with MR or PANX1 siRNA. Similar results were observed after treatment with apyrase or AZ10606120 in the coculture system. scRNA-seq analysis further identified the activation of P2X7\/NLRP3-related pyroptosis pathway in macrophages from DOCA-salt mice. In conclusion, TECs play a critical role in macrophage pyroptosis in Aldo-induced renal injury. eATP is a key messenger involved in TEC\u2013macrophage crosstalk. PANX1-eATP-P2X7 signaling mediates TEC\u2012macrophage interactions to exacerbate Aldo-driven renal inflammation in hypertension.<\/jats:p>","DOI":"10.1038\/s41419-026-08951-3","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T07:33:58Z","timestamp":1785828838000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tubular epithelial cells promote macrophage pyroptosis through PANX1-extracellular ATP-P2X7 signaling in aldosterone-dependent renal injury"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3810-5863","authenticated-orcid":false,"given":"Chongjian","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongkun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8492-4798","authenticated-orcid":false,"given":"Yan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5352-3301","authenticated-orcid":false,"given":"Yilei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4307-8014","authenticated-orcid":false,"given":"Zhiyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9011-361X","authenticated-orcid":false,"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"8951_CR1","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/S0140-6736(21)01330-1","volume":"398","author":"Collaboration NCDRF.","year":"2021","unstructured":"Collaboration NCDRF. 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