ArticleJournal of the American Society of Nephrology : JASN2015
Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease.
Article in Journal of the American Society of Nephrology : JASN, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 40 citations in OpenAlex.
- Tri-domain proteins 27 alleviates ischemia-reperfusion injury-induced acute kidney injury by promoting Gli-like transcription factor 1 expression via the inhibition of polycomb repressive complex 2 activity.Journal of cell communication and signaling · 2025Article
- Identification of the prognostic effect of mitophagy-related genes in acute myeloid leukemia.Frontiers in immunology · 2025Article
- FHL2 in arterial medial calcification in chronic kidney disease.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2024Article
- Effects of the FHL2 gene on the development of subcutaneous and intramuscular adipocytes in goats.BMC genomics · 2024Article
- Proximal tubular FHL2, a novel downstream target of hypoxia inducible factor 1, is a protector against ischemic acute kidney injury.Cellular and molecular life sciences : CMLS · 2024Article
- The chromatin landscape of healthy and injured cell types in the human kidney.Nature communications · 2024Article
- The roles of FHL2 in cancer.Clinical and experimental medicine · 2023Review
- FHL2 Genetic Polymorphisms and Pro-Diabetogenic Lipid Profile in the Multiethnic HELIUS Cohort.International journal of molecular sciences · 2023Article
- Modeling SILAC Data to Assess Protein Turnover in a Cellular Model of Diabetic Nephropathy.International journal of molecular sciences · 2023Article
- Non-canonical Wnt/calcium signaling is protective against podocyte injury and glomerulosclerosis.Kidney international · 2022Article
- Article
- How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease.Cells · 2021Review
- MRTF: Basic Biology and Role in Kidney Disease.International journal of molecular sciences · 2021Review
- WNT-β-catenin signalling - a versatile player in kidney injury and repair.Nature reviews. Nephrology · 2021Review
- TRIM18-Regulated STAT3 Signaling PathwayFrontiers in physiology · 2021Article
- Epigenetic Histone Modifications in the Pathogenesis of Diabetic Kidney Disease.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Review
- Ligustilide alleviates podocyte injury via suppressing the SIRT1/NF-κB signaling pathways in rats with diabetic nephropathy.Annals of translational medicine · 2020Article
- Deletion of FHL2 in fibroblasts attenuates fibroblasts activation and kidney fibrosis via restraining TGF-β1-induced Wnt/β-catenin signaling.Journal of molecular medicine (Berlin, Germany) · 2020Article
- Gene expression-based analysis identified NTNG1 and HGF as biomarkers for diabetic kidney disease.Medicine · 2020Observational
- Diabetic kidney diseases revisited: A new perspective for a new era.Molecular metabolism · 2019Review
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/β-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-β1, activated FHL2 protein and Wnt/β-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/β-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2(+/+) mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2(+/+) mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactions with β-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/β-catenin-induced podocytopathy.
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