{"doi":"10.34067/kid.0000000776","title":"Activin A Antagonism with Follistatin Reduces Kidney Fibrosis, Injury, and Cellular Senescence-Associated Inflammation in Murine Diabetic Kidney Disease","abstract":"Key Points Activin A is implicated in profibrotic and prosenescent kidney injury and correlates with kidney injury markers in animals and humans. Follistatin, through activin A antagonism, reduces senescence burden, macrophage infiltration, and proinflammatory pathway activation in murine diabetic kidney disease. Follistatin and other antagonists of activin A signaling pathways may be promising, novel therapeutics for diabetic kidney disease. Background Circulating activin A, an inflammatory mediator implicated in profibrotic kidney injury and cellular senescence-induced adipose tissue dysfunction, is increased in human diabetic kidney disease (DKD) and directly correlates with kidney dysfunction. We tested the hypothesis that activin A increases kidney injury, senescent cell abundance, and macrophage infiltration in DKD and antagonism through follistatin (FS) therapy diminishes these effects. Methods An accelerated nephropathy type 2 diabetes (db/db) mouse model was generated by implantation of angiotensin II-loaded osmotic minipumps resulting in increased albuminuria and glomerular and tubular injury. Kidney repair effects of FS (5 µ g intraperitoneal; two doses) were assessed through markers of kidney injury, fibrosis, inflammation, cellular senescence, and macrophage infiltration. In vitro studies examined antiactivin effects of FS on high glucose-exposed human monocytes, renal fibroblasts, and renal tubule epithelial cells. Results Activin A antagonism with FS reduced senescence (p19), proinflammatory (including senescence-associated secretory phenotype), and profibrotic markers including activin A. FS improved kidney morphology, restored podocyte markers (nephrin and Wilms tumor-1), and reduced kidney injury biomarkers, albuminuria and kidney fibrosis. FS decreased kidney macrophage and leukocyte infiltration and absent in melanoma 2 inflammasome activation. FS seemed to suppress inflammation through the toll-like receptor-4/NF kappa-light-chain-enhancer of activated B cells pathway in vivo further supported in human macrophages in vitro . In addition, FS reduced hyperglycemia-induced renal fibroblast activation and renal tubule epithelial cell senescence in vitro . Conclusions Activin A is a mediator of kidney injury through macrophage-associated inflammation in murine DKD. FS acts through senomorphic activities which inhibit profibrotic, proinflammatory, and prosenescence signaling by activin A. Hence, antiactivin targeting may aid in the development of a promising, novel therapeutic for DKD.","journal":"Kidney360","year":2025,"id":513254,"datarank":0.4263564296341292,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0666721387143735,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0666721387143735,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":7,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT01519349","NCT02354781","NCT02262455","NCT02848131","NCT03325322"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1083047,"name":"Zachary K. Snow","orcid":null,"position":1,"is_corresponding":false},{"id":1374948,"name":"C. Zinn","orcid":null,"position":2,"is_corresponding":false},{"id":1374949,"name":"Cody Gowan","orcid":null,"position":3,"is_corresponding":false},{"id":256713,"name":"Sabena M. Conley","orcid":null,"position":4,"is_corresponding":false},{"id":1374298,"name":"Anastasia L. Bratulin","orcid":"0000-0001-9263-0891","position":5,"is_corresponding":false},{"id":1374299,"name":"Khaled Elhusseiny","orcid":"0000-0002-2230-2160","position":6,"is_corresponding":false},{"id":233686,"name":"Jordan D. Miller","orcid":"0000-0002-9868-4097","position":7,"is_corresponding":false},{"id":106953,"name":"Tamar Tchkonia","orcid":"0000-0003-4623-7145","position":8,"is_corresponding":false},{"id":106952,"name":"James L. Kirkland","orcid":"0000-0003-1676-4905","position":9,"is_corresponding":false},{"id":253564,"name":"Lilach O. Lerman","orcid":"0000-0002-3271-3887","position":10,"is_corresponding":false},{"id":253557,"name":"LaTonya J. Hickson","orcid":"0000-0002-7485-336X","position":11,"is_corresponding":false},{"id":1374297,"name":"Xiaohui Bian","orcid":"0009-0008-1952-0141","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:48:17.908238Z","pmid":"40152935","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}