Epigenetic therapeutics attenuate kidney injury and fibrosis by restoring the expression of epigenetically reprogrammed fibrogenic genes and signaling pathways

Abstract

Kidney fibrosis is a commonly observed pathological condition during development of chronic kidney disease. Therapeutic options currently available are effective only in slowing the progression of kidney fibrosis and there is no cure for this disease. Aberrant expression and excessive accumulation of extracellular matrix (ECM) proteins in the peritubular space is a characteristic pathological feature of fibrotic kidney. However, the molecular basis of aberrant regulation of fibrotic genes in kidneys is not clear. In this context, this study aimed to evaluate the role of epigenetic reprogramming in kidney fibrosis. Folic acid (FA)-induced acute kidney injury (AKI) and kidney fibrosis in mice as an in vivo model and long-term arsenic or FA-exposed fibrogenic HK-2 cells as an in vitro model were used to evaluate the role of DNA methylation and histone modifications in fibrosis. DNA demethylating agent 5aza2 deoxycytidine (5-aza-2-dC) and histone deacetylase inhibitor Trichostatin A (TSA) were used to treat FA-injected mice. Results of histopathological and immunofluorescence staining of kidney tissue, serum albumin- creatinine levels, body weight, and gene expression analysis revealed significant protective effects of 5-aza-2-dC and TSA in FA-induced AKI and fibrosis. Insignificant change in the expression of N-cadherin whereas a significant decrease in E-cadherin as well as an increase in the expression of Vimentin and α-SMA suggest partial EMT associated with fibrosis. Aberrant expression of epithelial-mesenchymal-transition (EMT) and ECM-regulators (MMP2, Smad7, and TIMP3) as well as fibrogenic signaling pathways (Notch, TGF-beta, and Wnt signaling), and their restoration by 5-aza-2-dC and TSA treatments suggest epigenetic reprogramming of these genes and signaling pathways during FA-induced fibrosis. In summary, this study provides new information on the role of epigenetic reprogramming of fibrogenic genes and signaling pathways during the development of kidney fibrosis. Attenuation of fibrosis after 5-aza-2-dC and TSA treatments suggest the promise of these epigenetic-based therapeutics in the clinical management of this disease.