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

Version 2 2024-06-19, 16:33
Version 1 2023-02-10, 04:49
journal contribution
posted on 2024-06-19, 16:33 authored by MT Coughlan, Mark ZiemannMark Ziemann, A Laskowski, TM Woodruff, SM Tan
AbstractDespite 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.

History

Journal

Scientific Reports

Volume

12

Article number

20278

Pagination

20278-

Location

England

ISSN

2045-2322

eISSN

2045-2322

Language

en

Publication classification

C1 Refereed article in a scholarly journal

Issue

1

Publisher

Springer Science and Business Media LLC