Abstract
Mounting evidence indicates that an increase in histone deacetylation contributes to renal fibrosis. Although inhibition of histone deacetylase (HDAC) can reduce the extent of fibrosis, whether HDAC inhibitors exert the antifibrotic effect through modulating the phenotypes of macrophages, the key regulator of renal fibrosis, remains unknown. Moreover, the functional roles of the M2 macrophage subpopulation in fibrotic kidney diseases remain incompletely understood. Herein, we investigated the role of HDAC inhibitors on renal fibrogenesis and macrophage plasticity. We found that HDAC inhibition by trichostatin A (TSA) reduced the accumulation of interstitial macrophages, suppressed the activation of myofibroblasts and attenuated the extent of fibrosis in obstructive nephropathy. Moreover, TSA inhibited M1 macrophages and augmented M2 macrophage infiltration in fibrotic kidney tissue. Interestingly, TSA preferentially upregulated M2c macrophages and suppressed M2a macrophages in the obstructed kidneys, which was correlated with a reduction of interstitial fibrosis. TSA also repressed the expression of proinflammatory and profibrotic molecules in cultured M2a macrophages and inhibited the activation of renal myofibroblasts. In conclusion, our study was the first to show that HDAC inhibition by TSA alleviates renal fibrosis in obstructed kidneys through facilitating an M1 to M2c macrophage transition.
Highlights
Chronic kidney disease (CKD) is an emerging global public health issue with a prevalence rate of 10% to 12% worldwide [1]
The area of F4/80-positive macrophage infiltrate correspondingly increased in the day 14 obstructed kidneys (Figure 1), indicating that interstitial macrophages did play an essential role in the development of renal fibrosis
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Summary
Chronic kidney disease (CKD) is an emerging global public health issue with a prevalence rate of 10% to 12% worldwide [1]. Regardless of the etiologies of renal diseases, unresolved renal insult engages an excessive deposition of extracellular matrix in the tubulointerstitium, thereby bringing about end-stage renal disease [2]. Tubulointerstitial fibrosis is the final common pathway of all kidney diseases and, represents the major determinant of renal function decline [2]. A wealth of studies has indicated that renal function decline correlates well with the increasing risks for all-cause mortality, cardiovascular events and hospitalization [1,3,4]. Despite that current available therapies have targeted traditional risk factors for renal function decline—namely, hypertension, hyperglycemia and hyperlipidemia, nearly half of CKD patients still experience progressive renal function decline and eventual end-stage renal disease [5]. A novel treatment modality to tackle renal fibrosis and halt the progression of CKD is urgently needed
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