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.

Intervention treatment reducing cellular senescence inhibits tubulointerstitial fibrosis in diabetic mice following acute kidney injury

“…Recent animal model studies have indicated that other molecular mechanisms such as complement activation of the C5a receptor and pentraxin 3-induced mitochondrial dysfunction play a role in the development of senescence in kidney tubules in models of CKD involving diabetes or ischemic reperfusion injury [ 31 , 32 ]. These mechanisms were not examined in our evaluation of senotherapies in mice with diabetes and IRI.…”

Machine learning-based identification of biomarkers associated with NEBL in diabetic nephropathy

“…Moreover, ndings certi ed that valproic acid mitigated the diabetes-induced upregulation of complement C5a receptors, concurrently diminishing indicators of cellular senescence and the senescence-associated secretory phenotype. The attenuation of cellular senescence in the diabetic context assumes signi cance, given its implication in the pathogenesis of diabetic kidney disease 35 . Consequently, therapeutic interventions targeting cellular senescence, such as complement inhibitors, emerge as a novel and promising avenue for the treatment of diabetic kidney disease.…”

Therapeutic Potential of Targeting Complement C5a Receptors in Diabetic Kidney Disease

“…Emerging research suggests C5a may play a role as an epigenetic mediator capable of modulating the expression of genes involved in cellular senescence pathways [88,89]. C5a stimulation in renal tubular epithelial cells has been found to upregulate gene expression of senescence mediators, particularly mediators from the Wnt/β-catenin pathway [88], which is associated with the progression of AKI to chronic kidney disease, including DKD [90,91].…”

“…C5a stimulation in renal tubular epithelial cells has been found to upregulate gene expression of senescence mediators, particularly mediators from the Wnt/β-catenin pathway [88], which is associated with the progression of AKI to chronic kidney disease, including DKD [90,91]. Moreover, inhibition of C5aR1 with PMX53 attenuates cortical expression of genes involved in cellular senescence, in addition to reducing markers of the inflammatory senescenceassociated secretory phenotype (SASP) in streptozotocin-induced diabetic mice [89]. Thus, in addition to the direct effects of C5a/C5aR1 signaling in inflammatory cells in terms of chemotaxis and the release of chemokines and cytokines, this axis may also exacerbate renal inflammation and injury through modulating cellular senescence.…”