{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T03:20:46Z","timestamp":1768015246136,"version":"3.49.0"},"reference-count":55,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":2329,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:p>Proteinuria is an important cause of tubulointerstitial damage. Anti-proteinuric interventions are not always successful, and residual proteinuria often leads to renal failure. This indicates the need for additional treatment modalities by targeting the harmful downstream consequences of proteinuria. We previously showed that proteinuria triggers renal lymphangiogenesis before the onset of interstitial inflammation and fibrosis. However, the interrelationship of these interstitial events in proteinuria is not clear yet. To this end, we specifically blocked lymphangiogenesis (anti-VEGFR3 antibody), monocyte\/macrophage influx (clodronate liposomes) or lymphocyte and myofibroblast influx (S1P agonist FTY720) separately to investigate the role and the possible interaction of each of these phenomena in tubulointerstitial remodeling in proteinuric nephropathy. Proteinuria was induced in three-month old male Wistar rats by adriamycin injection. After 6 weeks, when proteinuria has developed, rats were treated for another 6 weeks by anti-VEGFR3 antibody, clodronate liposomes, and FTY720 up to week 12. In proteinuric rats, lymphangiogenesis, influx of macrophages, T cells and myofibroblasts, and collagen III deposition and interstitial fibrosis significantly increased at week 12 vs. week 6. Anti-VEGFR3 antibody prevented lymphangiogenesis in proteinuric rats, however without significant effects on inflammatory and fibrotic markers, and proteinuria. Clodronate liposomes inhibited macrophage influx, partly reduced myofibroblast expression; however, neither significantly prevented the development of lymphangiogenesis, nor fibrotic markers and proteinuria. FTY720 prevented myofibroblast accumulation and T cell influx and interstitial fibrosis, partially declined macrophage number and proteinuria; however, it did not influence significantly on lymphangiogenesis and collagen III deposition. This study showed that proteinuria-induced interstitial fibrosis cannot be halted by blocking lymphangiogenesis or influx of macrophages. On the other hand, FTY720 treatment could prevent T-cells influx, myofibroblasts accumulation and interstitial fibrosis, but not renal lymphangiogenesis and proteinuria. We conclude that tubulointerstitial fibrosis and inflammation are separate from lymphangiogenesis, at least under proteinuric conditions.<\/jats:p>","DOI":"10.1242\/dmm.018580","type":"journal-article","created":{"date-parts":[[2015,5,15]],"date-time":"2015-05-15T01:22:09Z","timestamp":1431652929000},"source":"Crossref","is-referenced-by-count":9,"title":["Targeting tubulointerstitial remodeling in experimental proteinuric nephropathy"],"prefix":"10.1242","author":[{"given":"Saleh","family":"Yazdani","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryanne S.","family":"Hijmans","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fariba","family":"Poosti","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, Division of Pathology, University of Groningen and University Medical Center Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy","family":"Dam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerjan","family":"Navis","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry","family":"van Goor","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, Division of Pathology, University of Groningen and University Medical Center Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob","family":"van den Born","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","reference":[{"key":"2021042612494251900_DMM018580C1","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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