{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:06:28Z","timestamp":1790816788133,"version":"4.1.0"},"reference-count":142,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"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. Pharmacol."],"abstract":"<jats:p>Proteinuria is a well-established risk factor for chronic kidney disease progression, and its reduction is associated with improved kidney outcomes. During proteinuric chronic kidney diseases, the abnormal passage of plasma-derived proteins through the damaged glomerular filtration barrier can lead to the activation of various pathophysiological processes in the tubular compartment. These mainly comprise complement activation and excessive proximal tubule reuptake of filtered proteins, such as albumin and associated lipids, which trigger cytotoxic effects through the dysregulation of multiple signaling pathways. Collectively, these signaling events can induce proximal tubular cell apoptosis or the acquisition of injury phenotypes, characterized by the paracrine release of bioactive substances that promote infiltration of immune cells and fibroblast-to-myofibroblast differentiation, eventually contributing to the development of tubulointerstitial fibrosis and progressive loss of kidney function. In this review, we provided an up-to-date overview of the complex mechanisms behind the toxic effects of ultrafiltered proteins on the tubulointerstitium under proteinuric conditions. The mechanistic insights that have been gained recently could be valuable for the future development of new classes of drugs to be used in combination with, or as an alternative to, the currently approved anti-proteinuric treatments in patients who are poorly responsive or unable to tolerate them, respectively.<\/jats:p>","DOI":"10.3389\/fphar.2026.1837046","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:20:16Z","timestamp":1779949216000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Tubulointerstitial inflammation and fibrosis induced by proteinuria: fresh insights"],"prefix":"10.3389","volume":"17","author":[{"given":"Monica","family":"Cortinovis","sequence":"first","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS","place":["Bergamo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Remuzzi","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS","place":["Bergamo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norberto","family":"Perico","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS","place":["Bergamo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1046\/j.1523-1755.2002.00380.x","article-title":"Proximal tubular cells promote fibrogenesis by TGF-b1-mediated induction of peritubular myofibroblasts","volume":"61","author":"Abbate","year":"2002","journal-title":"Kidney Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1681\/ASN.2006040377","article-title":"How does proteinuria cause progressive renal damage?","volume":"17","author":"Abbate","year":"2006","journal-title":"J. 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