ArticleKidney & blood pressure research2019
Rac1 GTPase Inhibition Blocked Podocyte Injury and Glomerular Sclerosis during Hyperhomocysteinemia via Suppression of Nucleotide-Binding Oligomerization Domain-Like Receptor Containing Pyrin Domain 3 Inflammasome Activation.
Article in Kidney & blood pressure research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 20 citations in OpenAlex.
- Mechanistic Role of Astrocytic Rac1 Protein in Alzheimer's Disease.Aging and disease · 2025Review
- Circulating RAC1 contributed to steroid-sensitive nephrotic syndrome: Mendelian randomization, single-cell RNA-sequencing, proteomic, and experimental evidence.Renal failure · 2024Article
- Pathomechanisms of Diabetic Kidney Disease.Journal of clinical medicine · 2023Review
- Ion channels and channelopathies in glomeruli.Physiological reviews · 2023Review
- Mineralocorticoid Receptor-Associated Mechanisms in Diabetic Kidney Disease and Clinical Significance of Mineralocorticoid Receptor Antagonists.American journal of nephrology · 2023Review
- MicroRNA-223 downregulation promotes HBx-induced podocyte pyroptosis by targeting the NLRP3 inflammasome.Archives of virology · 2022Article
- Are Alterations in DNA Methylation Related to CKD Development?International journal of molecular sciences · 2022Review
- Activation of the NLRP3 inflammasome by RAC1 mediates a new mechanism in diabetic nephropathy.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Article
- miR-30a-5p promotes glomerular podocyte apoptosis via DNMT1-mediated hypermethylation under hyperhomocysteinemia.Acta biochimica et biophysica Sinica · 2022Article
- RAGE pathway activation and function in chronic kidney disease and COVID-19.Frontiers in medicine · 2022Review
- Metabolic Dysfunction in the Regulation of the NLRP3 Inflammasome Activation: A Potential Target for Diabetic Nephropathy.Journal of diabetes research · 2022Review
- SIRT1 Alleviates Aldosterone-Induced Podocyte Injury by Suppressing Mitochondrial Dysfunction and NLRP3 Inflammasome Activation.Kidney diseases (Basel, Switzerland) · 2021Article
- Role of γ-adducin in actin cytoskeleton rearrangements in podocyte pathophysiology.American journal of physiology. Renal physiology · 2021Article
- NLRP3 Inflammasome in Metabolic-Associated Kidney Diseases: An Update.Frontiers in immunology · 2021Review
- Inflammasome activation in podocytes: a new mechanism of glomerular diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2020Review
- Nitrative Stress-Related Autophagic Insufficiency Participates in Hyperhomocysteinemia-Induced Renal Aging.Oxidative medicine and cellular longevity · 2020Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Elevated homocysteine (Hcy) levels have been shown to activate nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome leading to podocyte dysfunction and glomerular injury. However, it remains unclear how this inflammasome activation in podocytes is a therapeutic target for reversal of glomerular injury and ultimate sclerosis. The present study tested whether inhibition of Rac1 GTPase activity suppresses NLRP3 inflammation activation and thereby blocks podocyte injury induced by elevated Hcy. In cultured podocytes, we found that L-Hcy (the active Hcy form) stimulated the NLRP3 inflammasome formation, as shown by increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1, which was accompanied by increased interleukin-1β production and caspase-1 activity, indicating NLRP3 inflammasome activation. Rac1 activator, uridine triphosphate (UTP), mimicked L-Hcy-induced NLRP3 inflammasome activation, while Rac1 inhibitor NSC23766 blocked it. This Rac1 inhibition also prevented L-Hcy-induced podocyte dysfunction. All these effects were shown to be mediated via lipid raft redox signaling platforms with nicotinamide adenine dinucleotide phosphate oxidase subunits and consequent O2- production. In animal studies, hyperhomocysteinemia (hHcy) induced by folate-free diet was shown to induce NLRP3 inflammasome formation and activation in glomeruli, which was also mimicked by UTP and inhibited by NSC23766 to a comparable level seen in Nlrp3 gene knockout mice. These results together suggest that Rac1 inhibition protects the kidney from hHcy-induced podocyte injury and glomerular sclerosis due to its action to suppress NLRP3 inflammasome activation in podocytes.
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