{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T19:46:35Z","timestamp":1778615195213,"version":"3.51.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Aristolochic acid (AA) is a toxin that induces DNA damage in tubular epithelial cells of the kidney and is the cause of Balkan Nephropathy and Chinese Herb Nephropathy. In cultured tubular epithelial cells, AA induces a pro-fibrotic response <jats:italic>via<\/jats:italic> the c-Jun amino terminal kinase (JNK) signaling pathway. This study investigated the <jats:italic>in vivo<\/jats:italic> role of JNK signaling with a JNK inhibitor (CC-930) in mouse models of acute high dose AA-induced kidney injury (day 3) and renal fibrosis induced by chronic low dose AA exposure (day 22). CC-930 treatment inhibited JNK signaling and protected from acute AA-induced renal function impairment and severe tubular cell damage on day 3, with reduced macrophage infiltration and expression of pro-inflammatory molecules. In the chronic model, CC-930 treatment inhibited JNK signaling but did not affect AA-induced renal function impairment, tubular cell damage including the DNA damage response and induction of senescence, or renal fibrosis; despite a reduction in the macrophage pro-inflammatory response. In conclusion, JNK signaling contributes to acute high dose AA-induced tubular cell damage, presumably <jats:italic>via<\/jats:italic> an oxidative stress-dependent mechanism, but is not involved in tubular atrophy and senescence that promote chronic kidney disease caused by ongoing DNA damage in chronic low dose AA exposure.<\/jats:p>","DOI":"10.3389\/fphys.2021.599114","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T20:31:11Z","timestamp":1613248271000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury"],"prefix":"10.3389","volume":"12","author":[{"given":"Fan","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elyce","family":"Ozols","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank Y.","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khai Gene","family":"Leong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greg H.","family":"Tesch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Nikolic-Paterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1111\/j.1523-1755.2004.00500.x","article-title":"Activation of ERK or inhibition of JNK ameliorates H2O2 cytotoxicity in mouse renal proximal tubule cells","volume":"65","author":"Arany","year":"2004","journal-title":"Kidney Int."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.tox.2009.07.014","article-title":"Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy","volume":"264","author":"Bakhiya","year":"2009","journal-title":"Toxicology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"364","DOI":"10.3390\/toxins12060364","article-title":"Therapeutic targeting of aristolochic acid induced uremic toxin retention, SMAD 2\/3 and JNK\/ERK pathways in tubulointerstitial fibrosis: nephroprotective role of propolis in chronic kidney disease","volume":"12","author":"Chang","year":"2020","journal-title":"Toxins (Basel)"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/aps.2009.197","article-title":"Microarray analysis reveals the inhibition of nuclear factor-kappa B signaling by aristolochic acid in normal human kidney (HK-2) cells","volume":"31","author":"Chen","year":"","journal-title":"Acta Pharmacol. 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