{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:28:51Z","timestamp":1788280131995,"version":"build-2803163510"},"reference-count":113,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD) globally. Beyond metabolic and haemodynamic stress, the complement system has emerged as a contributor to glomerular and tubulointerstitial injury. In type 1 diabetes mellitus (T1DM), complement proteins contribute through autoimmune mechanisms, while in type 2 diabetes mellitus (T2DM) they are linked to insulin resistance. In both, complement activation promotes micro- and macrovascular complications through inflammatory pathways that accelerate DN progression. This review summarises the current evidence on the role of complement activation in diabetic nephropathy (DN). First, we outline the mechanisms by which the complement system is activated through the lectin pathway (in which mannoses bind to modified glycosylation structures), the classical pathway (in which C1q recognises immune complexes\/damaged self), and the alternative pathway (in which C3 ticks over and amplifies on damaged renal surfaces). Next, we consider the roles of their effector molecules (C3a, C5a, and C5b-9\/MAC), and the consequences of regulatory dysfunction (e.g., CD59 dysfunction). When integrated with findings from renal histology, blood and urine biomarkers enable us to evaluate the correlation between prognosis, disease severity, and progression. We will also discuss therapeutic implications, including the rationale behind selective complement inhibition and future intervention strategies.<\/jats:p>","DOI":"10.3390\/jcm14238589","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T16:20:29Z","timestamp":1765210829000},"page":"8589","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Role of Complement Activation in Diabetic Nephropathy: Current Insights and Future Directions"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6625-9571","authenticated-orcid":false,"given":"Nikolaos","family":"Kotsalas","sequence":"first","affiliation":[{"name":"Athens Naval and Veterans Hospital, Deinokratous 70, 11521 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadni","family":"Fouza","sequence":"additional","affiliation":[{"name":"5th Surgical Department, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Daoudaki","sequence":"additional","affiliation":[{"name":"Laboratory of Biological Chemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","unstructured":"Cowie, C.C., Casagrande, S.S., and Menke, A. 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