Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease

Abstract

Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation-Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A. This inhibition up-regulated Klotho mainly through an enhancement of PPARγ acetylation, stimulation of PPARγ binding to Klotho promoter, and PPARγ-dependent increase in Klotho transcription, with a substantial control of the regulation occurring via PPARγ acetylations on K240 and K265. Consistently trichostatin A-induced reversal of Klotho loss and renoprotective effects were abrogated in PPARγ knockout mice, supporting that PPARγ is an essential acetylation target for Klotho restoration and renal protection. Intriguingly, the kidneys of adenine-fed CKD mice displayed deregulated HDAC3 up-regulation. Selective HDAC3 inhibition effectively alleviated Klotho loss and kidney injury, whereas the protective effects were largely abolished when Klotho was knocked down by siRNA, suggesting that aberrant HDAC3 and Klotho loss are crucial components involved in the renal damage of mice with CKD. Our study identified an important signaling cascade and key components contributing to the pathogenesis of CKD. Thus, targeting Klotho loss by HDAC3 inhibition has promising therapeutic potential for the reduction of CKD progression.

Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis

“…Because pan-HDAC inhibitors are either advancing through clinical trials or are already approved for clinical use in the treatment of malignancy, specific inhibition of class IIa HDACs may also become a therapeutic option for the treatment of renal fibrosis and other fibrotic disorders in the future. (4,5,7,9) in renal tubular cells. Increased class IIa HDACs leads to activation of TGF-b/Smad3 and NF-kB signaling, up-regulation of MMP-2/9, and downregulation of klotho and BMP-7.…”

“…At the same time, renal fibrogenesis can also be induced and accelerated by down-regulation of antifibrotic molecules. It has been reported that expression of some antifibrotic molecules such as bone morphogenetic protein 7 (BMP-7) (8) and klotho (9) are reduced in renal epithelial cells during the course of renal fibrosis or in response to a TGF-b1 challenge (10). BMP-7 is a member of the TGF-b superfamily that can offset the profibrotic effects of TGF-b1 (11)(12)(13); the klotho gene encodes a single-pass transmembrane protein whose deficiency promotes the transition of acute kidney injury to CKD and accelerates uremic cardiomyopathy and vascular calcification (14,15).…”

PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice

“…Wild type C57BL/6 mice were purchased from Model Animal Research Center of Nanjing University. Generation of inducible PPARγ knockout mice (PPARγ fl/fl/ Cre-ERT2 ) has been described previously 21. Briefly, PPARγ-floxed mice (PPARγ fl/fl , B6.129-Pparg tm2Rev /J, stock number: 004584, Jackson Laboratory, Bar Harbor, USA), served as PPARγ wild-type control (PPARγWT), were bred with transgenic Cre-ERT2 mice (B6.Cg-Ndor1 Tg(UBC-cre/ERT2)1Ejb /1J), stock number: 007001) expressing an cytoplasm-tethered Cre-ERT2 fusion protein (ERT2, the mutated ligand binding domain of oestrogen receptor) to yield the tamoxifen-inducible PPARγ knockout mice PPARγ fl/fl/Cre-ERT2 (PPARγKO).…”

Application of Histone Deacetylase Inhibitors in Renal Interstitial Fibrosis

“…In a mouse model of diabetic kidneys diseases (DKD), the activity of HDAC-1, -2, and -4 was found to be elevated in STZ-inducted renal cortex, while the activity of HDAC-3, -5, and -8 was not significantly changed [38]. In the kidneys of adenine-fed CKD mice, HDAC3 was found to be upregulated, and selective HDAC3 inhibition effectively alleviated kidney injury [39]. In angiotensin II-infused mice, hypertensive stimuli enhanced the expression of HDAC6, and the inhibition of HDAC6 prevented fibrosis and inflammation [40].…”