{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:46:30Z","timestamp":1760060790813,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T00:00:00Z","timestamp":1758412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013704","name":"CONACYT","doi-asserted-by":"publisher","award":["A1-S-8731","2023-2024-190","IN204123"],"award-info":[{"award-number":["A1-S-8731","2023-2024-190","IN204123"]}],"id":[{"id":"10.13039\/501100013704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013704","name":"CBF","doi-asserted-by":"publisher","award":["A1-S-8731","2023-2024-190","IN204123"],"award-info":[{"award-number":["A1-S-8731","2023-2024-190","IN204123"]}],"id":[{"id":"10.13039\/501100013704","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UNAM-DGAPA-PAPIIT","award":["A1-S-8731","2023-2024-190","IN204123"],"award-info":[{"award-number":["A1-S-8731","2023-2024-190","IN204123"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the kidney participate in reabsorbing potassium (K+) and ammonium (NH4+) in the nephron, contributing to the acid\u2013base balance. Acidosis is a metabolic condition of renal tubular acidosis and chronic kidney disease. Acidosis stimulates the production of mitochondrial reactive oxygen species (mROS), activating protective mechanisms dependent on mitochondrial membrane potential (\u0394\u03c8m) such as autophagy. The HCN3 channel is expressed in the plasma membrane, mitochondria (mitoHCN3), and lysosomes (lysoHCN3) of the rat proximal tubule. In this work we aimed to investigate the role of HCN3 in autophagy, mROS production, and \u0394\u03c8m in cultured rat proximal tubule cells (NRK-52E) exposed to ammonium chloride (NH4Cl). NH4Cl arrested autophagic flux and produced extracellular acidosis and, under this condition, mitoHCN3 and lysoHCN3 were up-regulated. NH4Cl or\/and ZD7288, a specific blocker of HCN channels, enhanced mROS. ZD7288 in NH4Cl conditions at 24 h stimulated autophagy by reducing Beclin1, LC3BII, p62, and Parkin in an mROS- or \u0394\u03c8m independent pathway. Therefore, ZD7288 reverted NH4Cl inhibited autophagy through lysoHCN3 inhibition. Oxidative stress induced by H2O2 up-regulated mitoHCN3 expression, while Tiron had the opposite effect. In conclusion, inhibition of mito- and lysoHCN3 channels by ZD7288 can protect against mitochondrial oxidative stress and stimulate the lysosome\u2013autophagy pathway in response to NH4Cl treatment.<\/jats:p>","DOI":"10.3390\/ijms26189227","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T13:04:44Z","timestamp":1758546284000},"page":"9227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of HCN Channels Enhances Oxidative Stress and Autophagy of NRK-52E Cells Under NH4Cl Treatment"],"prefix":"10.3390","volume":"26","author":[{"given":"Zinaeli","family":"L\u00f3pez-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura I.","family":"Escobar","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Le\u00f3n-Aparicio","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8554-9076","authenticated-orcid":false,"given":"Abir\u00e1n Fernando","family":"Mej\u00eda-Peralta","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Padilla-Flores","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0768-3556","authenticated-orcid":false,"given":"Isabel","family":"Larre","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Salvador","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8264-0412","authenticated-orcid":false,"given":"Omar Noel","family":"Medina-Campos","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-4411","authenticated-orcid":false,"given":"Jos\u00e9","family":"Pedraza-Chaverri","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marisol","family":"de la Fuente-Granada","sequence":"additional","affiliation":[{"name":"Departamento Medicina Gen\u00f3mica y Toxicolog\u00eda Ambiental, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,21]]},"reference":[{"key":"ref_1","first-page":"289","article-title":"Distal Renal Tubular Acidosis: A Hereditary Disease with an Inadequate Urinary H+ Excretion","volume":"33","author":"Escobar","year":"2013","journal-title":"Nefrologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1681\/ASN.2019070677","article-title":"Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney Disease","volume":"31","author":"Wesson","year":"2020","journal-title":"J. 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