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Given that lysosome cathepsins participate in human pathobiology, we investigated the roles of cathepsin S (CatS) in chronic stress\u2010related renal damage and dysfunction in mice subjected to a 5\/6 nephrectomy surgery. A mouse model combining 5\/6 nephrectomy (5\/6Nx) surgery and chronic restrain stress (CRS) was applied to wild\u2010type (CatS\n                    <jats:sup>+\/+<\/jats:sup>\n                    ) and CatS knockout (CatS\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) mice. The CRS exacerbated the 5\/6Nx\u2010induced renal injury, blood\u2010pressure elevation, glomerulosclerosis, fibrosis, podocyte damage, and inflammatory macrophage infiltration while simultaneously increasing the renal CatS expression. Compared to the CatS\n                    <jats:sup>+\/+<\/jats:sup>\n                    mice, the CatS\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice exhibited attenuated CRS\u2010induced renal injury exacerbation manifested by improved renal function (urinary albumin) and blood pressure, reduced microstructure alterations, and lowered levels of renal inflammation (interleukin\u20101\u03b2, tumor necrosis factor\u2010\u03b1, galectin\u20103, angiotensin II type 1 receptor, monocyte chemoattractant protein\u20101, and Toll\u2010like receptor\u20102), oxidative stress (gp91\n                    <jats:sup>phox<\/jats:sup>\n                    , p22\n                    <jats:sup>phox<\/jats:sup>\n                    )\u2010related and apoptosis [cleaved caspase\u20103 (C\u2010caspase\u20103), cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    , and Bcl\u20102]\u2010related, extracellular remodeling (CatS, matrix metalloproteinase\u20109, and collagen types I and III)\u2010related molecular proteins and\/or genes. Pharmacological inhibition of CatS yielded the same conclusions. In mesangial cells, CatS overexpression and silencing, respectively, elevated or lowered C\u2010caspase\u20103 and cytochrome c levels, providing evidence that a mechanistic explanation of CatS\u2010caspase\u20103\/cytochrome\u2010mediated cell apoptosis in response to 5% stressed serum and oxidative stress. CatS inhibition appeared to ameliorate CRS\u2010related renal injury and hypertension development in mice that underwent 5\/6 nephrectomy surgery, possibly by lowering renal oxidative stress, inflammation, proteolysis, and apoptosis. CatS might thus become a potential therapeutic target for CRS\u2010related renal remodeling and hypertension in animals with CKD.\n                  <\/jats:p>","DOI":"10.1096\/fj.202601039r","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T15:15:08Z","timestamp":1780672508000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cathepsin S Deficiency Prevents Chronic Stress\u2010Related Renal Remodeling and Dysfunction in a Mouse 5\/6 Nephrectomy Injury Model"],"prefix":"10.1096","volume":"40","author":[{"given":"Hailong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology and Hypertension The Affiliated Hospital of Yanbian University (Yanbian Hospital)  Yanji Jilin China"},{"name":"General Internal Medicine Maternal and Child Health Hospital of Hubei Province Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei P.R. 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Anesthesiology Northern Jiangsu People's Hospital  Yangzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Ping","family":"Shi","sequence":"additional","affiliation":[{"name":"Jilin Provencial Key Laboratory of Stress and Cardiovascular Disease Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Kuzuya","sequence":"additional","affiliation":[{"name":"Meitetsu Hospital  Nagoya Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Umegaki","sequence":"additional","affiliation":[{"name":"Department of Community Health &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Hypertension The Affiliated Hospital of Yanbian University (Yanbian Hospital)  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