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In recent years, increasing evidence has suggested that EC undergoes an endothelial-to-mesenchymal transition (EndoMT), which might promote fibrosis. Adriamycin (ADR) induces glomerular endothelial dysfunction, which leads to progressive proteinuria in rodents. The activation of the vitamin D receptor (VDR) plays a crucial role in endothelial function modulation, cell differentiation, and suppression of the expression of fibrotic markers by regulating the production of nitric oxide (NO) by activating the endothelial NO synthase (eNOS) in the kidneys. This study aimed to evaluate the effect of paricalcitol treatment on renal endothelial toxicity in a model of CKD induced by ADR in rats and explore mechanisms involved in EC maintenance by eNOS\/NO, angiopoietins (Angs)\/endothelium cell-specific receptor tyrosine kinase (Tie-2, also known as TEK) and vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) axis. The results show that paricalcitol attenuated the renal damage ADR-induced with antiproteinuric effects, glomerular and tubular structure, and function protection. Furthermore, activation of the VDR promoted the maintenance of the function and structure of glomerular, cortical, and external medullary endothelial cells by regulating NO production. In addition, it suppressed the expression of the mesenchymal markers in renal tissue through attenuation of (transforming growth factor-beta) TGF-\u03b21\/Smad2\/3-dependent and downregulated of Ang-2\/Tie-2 axis. It regulated the VEGF\/VEGFR2 pathway, which was ADR-deregulated. These effects were associated with lower AT1 expression and VDR recovery to renal tissue after paricalcitol treatment. Our results showed a protective role of paricalcitol in the renal microvasculature that could be used as a target for treating the beginning of CKD.<\/jats:p>","DOI":"10.3390\/nu14245316","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T03:01:51Z","timestamp":1671073311000},"page":"5316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Paricalcitol Improves the Angiopoietin\/Tie-2 and VEGF\/VEGFR2 Signaling Pathways in Adriamycin-Induced Nephropathy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8827-7172","authenticated-orcid":false,"given":"Amanda Lima","family":"Deluque","sequence":"first","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz Magalh\u00e3es","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e1udia Silva","family":"Souza","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana L\u00edvia Dias","family":"Maciel","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helo\u00edsa Della Coletta","family":"Francescato","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleonice","family":"Giovanini","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5731-1219","authenticated-orcid":false,"given":"Lucas Ferreira","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1262-3486","authenticated-orcid":false,"given":"Francisco Jos\u00e9 Albuquerque","family":"de Paula","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrinology, Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14015-010, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto Silva","family":"Costa","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Pathology, Division of Nephrology, Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14015-010, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3486-9217","authenticated-orcid":false,"given":"Jos\u00e9","family":"Antunes-Rodrigues","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroendocrinology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terezila Machado","family":"Coimbra","sequence":"additional","affiliation":[{"name":"Laboratory of Renal Physiology, Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF-\u03b2: The Master Regulator of Fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. 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