{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:02:26Z","timestamp":1790240546913,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic kidney disease (CKD) is characterized by progressive tubulointerstitial inflammation and fibrosis, particularly affecting the proximal tubule. Both proximal tubular epithelial cells and interstitial fibroblasts contribute to CKD progression through cell\u2010cycle arrest and phenotypic transitions. The aim of the present study was to address whether lactic acidosis contributes to these processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human proximal tubular cells (HK\u20102 cells) and fibroblasts (CCDSk cells) were exposed to lactic acid, hydrochloric acid, or sodium lactate. Transcriptomic changes were assessed by RNA sequencing followed by GO term enrichment as well as canonical pathway and upstream\u2010regulator analyses. Predicted effects on the cell cycle were validated experimentally using BrdU incorporation and digital microscopy\u2010based cell\u2010cycle analysis. Protein expression of IL\u20106, c\u2010FOS, phospho\u2010JAK1 and JAK2, STAT3, SRF, and p38 was assessed by Western blot.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Transcriptomic analysis revealed synergistic effects of lactate and acidification on gene expression, which were associated with cell type\u2010specific phenotypic changes. Biological assays confirmed these predictions: HK\u20102 cells underwent a sustained G1 arrest with reduced DNA synthesis, while CCDSk cells displayed only a transient arrest resolving after 48\u2009h. Predictions further indicated that lactic acidosis amplifies these effects, driving fibrotic reprogramming in HK\u20102 cells and promoting a phenotypic switch of CCDSk cells toward an inflammatory state.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that extracellular lactic acidosis primes tubular cells for fibrotic remodeling and CCDSk cells for inflammatory activation, and may therefore represent an initiating microenvironmental trigger for maladaptive changes in CKD progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70302","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T07:50:28Z","timestamp":1788767428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Acidic Tubulointerstitial Microenvironment Delays Cell\u2010Cycle Progression in Proximal Tubule Cells and Fibroblasts and Synergizes With Lactate to Drive Phenotypic Alterations"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4179-9566","authenticated-orcid":false,"given":"Marie\u2010Christin","family":"Schulz","sequence":"first","affiliation":[{"name":"Julius\u2010Bernstein Institute of Physiology, Martin Luther University Halle\u2010Wittenberg  Halle Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4840-8940","authenticated-orcid":false,"given":"Virginie","family":"Dubourg","sequence":"additional","affiliation":[{"name":"Julius\u2010Bernstein Institute of Physiology, Martin Luther University Halle\u2010Wittenberg  Halle 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