Dataset Information

Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors.

ABSTRACT: Despite increasing knowledge about the factors involved in the progression of diabetic complications, diabetic kidney disease (DKD) continues to be a major health burden. Current therapies only slow but do not prevent the progression of DKD. Thus, there is an urgent need to develop novel therapy to halt the progression of DKD and improve disease prognosis. In our preclinical study where we administered a histone deacetylase (HDAC) inhibitor, valproic acid, to streptozotocin-induced diabetic mice, albuminuria and glomerulosclerosis were attenuated. Furthermore, we discovered that valproic acid attenuated diabetes-induced upregulation of complement C5a receptors, with a concomitant reduction in markers of cellular senescence and senescence-associated secretory phenotype. Interestingly, further examination of mice lacking the C5a receptor 1 (C5aR1) gene revealed that cellular senescence was attenuated in diabetes. Similar results were observed in diabetic mice treated with a C5aR1 inhibitor, PMX53. RNA-sequencing analyses showed that PMX53 significantly regulated genes associated with cell cycle pathways leading to cellular senescence. Collectively, these results for the first time demonstrated that complement C5a mediates cellular senescence in diabetic kidney disease. Cellular senescence has been implicated in the pathogenesis of diabetic kidney disease, thus therapies to inhibit cellular senescence such as complement inhibitors present as a novel therapeutic option to treat diabetic kidney disease.

SUBMITTER: Coughlan MT

PROVIDER: S-EPMC9700697 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors.

Coughlan Melinda T MT Ziemann Mark M Laskowski Adrienne A Woodruff Trent M TM Tan Sih Min SM

Scientific reports 20221124 1

Despite increasing knowledge about the factors involved in the progression of diabetic complications, diabetic kidney disease (DKD) continues to be a major health burden. Current therapies only slow but do not prevent the progression of DKD. Thus, there is an urgent need to develop novel therapy to halt the progression of DKD and improve disease prognosis. In our preclinical study where we administered a histone deacetylase (HDAC) inhibitor, valproic acid, to streptozotocin-induced diabetic mice ...[more]

PMID: 36434087

Similar Datasets

Project description:BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the decline of cognition and the presence of neuropathological changes including neuronal loss, neurofibrillary pathology and extracellular senile plaques. A neuroinflammatory process is also triggered and complement activation has been hypothesized to have a relevant role in this local inflammatory response. C5a, a proinflammatory anaphylatoxin generated after complement activation, exerts its chemotactic and inflammatory functions through the CD88 receptor while the more recently discovered C5L2 receptor has been postulated to have an anti-inflammatory role. Previously, we reported that a CD88 specific antagonist (PMX205) decreased the pathology and improved cognition in transgenic models of AD suggesting that C5a/C5aR interaction has an important role in the progression of the disease. METHODS:The present study characterizes the expression of the two receptors for C5a in human brain with confirmed post mortem diagnosis of vascular dementia (VD) or AD as well as age matched controls by immunohistochemistry and Western blot analysis using several antibodies against different epitopes of the human receptors. RESULTS:The CD88 and C5L2 antibodies revealed increased expression of both receptors in AD samples as compared to age-matched controls or VD brain tissue by Western blot and immunohistochemistry, using multiple antibodies and distinct cohorts of brain tissue. Immunostaining showed that both the C5L2 and CD88 antibodies similarly labeled abundant neurofibrillary tangles, neuropil threads and dystrophic neurites associated with plaques in the hippocampus and frontal cortex of AD cases. In contrast, little or no neuronal staining, tangles or dystrophic neurites associated with plaques were observed in control or VD brains. CD88 and C5L2 receptors are associated with both early (AT8) and mature (PHF1) neurofibrillary tangles and can be found either independently or colocalized with each other. CONCLUSIONS:The observed association of CD88 and C5L2 with neurofibrillary pathology suggests a common altered pathway of degradation.

Project description:PurposeEmerging evidences have indicated a role of the complement system in the pathogenesis of diabetic nephropathy (DN). Thus, this study was conducted to explore the complement system-related key biomarkers for patients with DN.MethodsDN microarray datasets were downloaded from the GEO database, followed by differentially expressed genes (DEGs) screening. Complement system-related genes (CSRGs) were searched from various databases. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to screen the DN-related genes, then the differential CSRGs (DCSRGs) were identified, followed by protein-protein interaction (PPI) network construction. In addition, key biomarkers were acquired by two machine learning algorithms, then immune infiltration analysis, Gene Set Enrichment Analysis (GSEA), and potential drugs screening were conducted. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting were utilized to detect the ITGB2 expression. Then the cell viability, inflammatory factors, and the expression of epithelial-mesenchymal transition (EMT) and fibrosis markers were determined by using Cell Counting Kit-8 (CCK-8) assay, enzyme linked immunosorbent assay (ELISA), western blotting assays, respectively.ResultsIn total, 1012 DEGs and 974 DN-related genes were screened, and intersection analysis of the three (DN-related genes, DEGs and CSRGs) yielded 13 intersection genes, which were considered as the DCSRGs. Subsequently, 2 key biomarkers were identified by machine learning, namely VWF and ITGB2. The VWF and ITGB2 were both enriched in the pathways of chemokine signaling pathway, CAMs, focal adhesion and natural killer cell-mediated cytotoxicity, and significantly correlated with the activated mast cells, resting NK cells, and macrophages. Also, VWF and ITGB2 were significantly related to the clinical features, including age, serum creatinine level, and GFR (MDRD). Besides, mRNA and protein expression levels of ITGB2 in HG-treated HK-2 cells were remarkably elevated. Moreover, the viability of HK-2 cells, expression of TNF-α, IL-6, IL-12, α-SMA, E-cadherin and vimentin in HK-2 cells changed by HG administration were reversed by ITGB2-silence.ConclusionComplement system-related gene ITGB2 was overexpressed in DN, and inhibition of ITGB2 attenuated EMT and inflammation in DN.

Dataset Information

Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors.

Publications

Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets