{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:51:35Z","timestamp":1792788695839,"version":"4.5.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","funder":[{"name":"National Key Clinical Specialty Discipline Construction Program of China"},{"name":"National Natural Science Foundation of China","award":["NO. 82222013"],"award-info":[{"award-number":["NO. 82222013"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["NO. 82470731"],"award-info":[{"award-number":["NO. 82470731"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the Key Program of the Natural Science Foundation of Human Province, China","award":["NO. 2025JJ30048"],"award-info":[{"award-number":["NO. 2025JJ30048"]}]},{"name":"Degree & Postgraduate Education Reform Project of Central South University","award":["NO. 2025JGB014"],"award-info":[{"award-number":["NO. 2025JGB014"]}],"id":[{"id":"https:\/\/ror.org\/00f1zfq44","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Vicerrector\u00eda de Investigaci\u00f3n y Estudios de Posgrado, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla","award":["NO. 2025JGYB031"],"award-info":[{"award-number":["NO. 2025JGYB031"]}],"id":[{"id":"https:\/\/ror.org\/03p2z7827","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Retinoic acid receptor responder protein 1 is upregulated in proximal tubular epithelial cells in CKD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Soluble retinoic acid receptor responder protein 1 drives fibrosis by binding KH RNA binding domain containing, signal transduction associated 1, recruiting steroid receptor coactivator kinase, and inducing signal transducer and activator of transcription 3 phosphorylation.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Kidney fibrosis is a hallmark of CKD, yet its underlying mechanisms remain incompletely understood. Retinoic acid receptor responder protein 1 (RARRES1) is largely restricted to podocytes in healthy kidneys but was upregulated within the tubulointerstitium in CKD. However, its functional contribution to kidney fibrosis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To assess the link between tubulointerstitial RARRES1 expression, eGFR, and fibrosis severity in patients with CKD, we analyzed multiple clinical datasets. RARRES1 upregulation in proximal tubular epithelial cells was confirmed in human CKD samples by immunofluorescence and RNAscope assays. Kidney fibrosis was evaluated in proximal tubule\u2013specific\n                      <jats:italic toggle=\"yes\">Rarres1<\/jats:italic>\n                      knockout mice and RARRES1-overexpressing mice after CKD induction, including unilateral ureteral obstruction and folic acid\u2013induced nephropathy. Mechanistically, mass spectrometry and coimmunoprecipitation, combined with truncation mutants, uncovered interactions among soluble RARRES1, KH RNA binding domain containing, signal transduction associated 1 (KHDRBS1), steroid receptor coactivator (Src) kinase, and phosphorylated signal transducer and activator of transcription 3 (STAT3). Pharmacologic blockade of STAT3 or Src kinase was used to evaluate the reversal of RARRES1-induced fibrotic phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Multiple datasets revealed that tubulointerstitial RARRES1 expression correlated with decreased eGFR and increased fibrosis severity in patients with CKD. Immunofluorescence and RNAscope confirmed RARRES1 upregulation specifically in proximal tubular epithelial cells in CKD. Proximal tubule\u2013specific knockout of\n                      <jats:italic toggle=\"yes\">Rarres1<\/jats:italic>\n                      significantly attenuated kidney fibrosis in two independent CKD models. Conversely, RARRES1-overexpressing mice showed aggravated kidney fibrosis compared with controls in the unilateral ureteral obstruction model. Soluble RARRES1 was identified as the key pathogenic form, with its plasma levels correlating with declining kidney function in patients with CKD. Mechanistically, soluble RARRES1 bound KHDRBS1, recruited Src kinase, and induced STAT3 phosphorylation at Tyr705, leading to upregulation of profibrotic factors. Inhibition of STAT3 or Src kinase partially reversed the fibrotic phenotype induced by RARRES1 overexpression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrated that RARRES1 played an important role in regulating kidney fibrosis through the KHDRBS1\/Src\/p-STAT3 signaling axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.0000001081","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:00:43Z","timestamp":1775750443000},"page":"1880-1894","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Retinoic Acid Receptor Responder Protein 1 Promotes Tubular Fibrosis via the KH RNA Binding Domain Containing, Signal Transduction Associated 1\/Steroid Receptor Coactivator\/p-Signal Transducer and Activator of Transcription 3 Axis"],"prefix":"10.1681","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0392-915X","authenticated-orcid":false,"given":"Lin","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5449-8375","authenticated-orcid":false,"given":"Yong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan and Chongqing Province, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7530-9051","authenticated-orcid":false,"given":"Baiyu","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya 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