Histone deacetylase inhibition ameliorates kidney injury by restoring fibroblast features to myofibroblasts.

AIMS: There are no effective strategies for treating chronic kidney disease (CKD) because of the limited understanding of its complex pathology. Fibrosis commonly develops and expands during CKD progression, making it a plausible therapeutic target against CKD. We have previously reported that kidney disease induces the myofibroblastic transformation of renal interstitial fibroblasts, which produce the erythroid growth factor erythropoietin, thereby promoting fibrosis through the production of extracellular matrix and leading to erythropoietin-deficiency anaemia. Since histone deacetylases (HDACs) govern cellular differentiation status, this study investigated whether HDAC inhibition could ameliorate renal fibrosis through restoring myofibroblasts to fibroblastic cells.

METHODS

Changes in the gene expression profile and morphology of a myofibroblast line derived from murine renal fibroblasts were assessed after incubation with HDAC inhibitors or inactivation of HDAC isoform expression. The effects of pharmacological HDAC inhibition were also evaluated using CKD model mice and primary-cultured renal myofibroblasts obtained from the urine of a patient with CKD.

KEY FINDINGS: HDAC inhibitors shifted the gene expression signature of myofibroblasts towards that of fibroblasts and induced morphological changes. HDAC2 knockdown partially recapitulated these effects, whereas HDAC1 knockdown failed because of cell death. HDAC inhibition significantly attenuated genes related to fibrosis and tubular damage, with similar trends histologically observed. In patient-derived renal myofibroblasts, HDAC inhibition suppressed profibrotic gene expression and restored erythropoietin gene expression.

SIGNIFICANCE: HDAC inhibition suppresses renal fibrosis through the induction of apoptosis and restores fibroblast features in myofibroblasts, potentially leading to the amelioration of tubular damage and erythropoietin insufficiency in patients with CKD.