Klotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney disease.
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.
['Lin|Wenjun|W|', 'Zhang|Qin|Q|', 'Liu|Lin|L|', 'Yin|Shasha|S|', 'Liu|Zhihong|Z|', 'Cao|Wangsen|W|']
D000107:Acetylation D000225:Adenine D000818:Animals D049109:Cell Proliferation D004195:Disease Models, Animal D018450:Disease Progression D015536:Down-Regulation D044127:Epigenesis, Genetic D005966:Glucuronidase D056572:Histone Deacetylase Inhibitors D006655:Histone Deacetylases D006801:Humans D006877:Hydroxamic Acids D007668:Kidney D000090265:Klotho Proteins D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D047495:PPAR gamma D011401:Promoter Regions, Genetic D011499:Protein Processing, Post-Translational D034741:RNA, Small Interfering D051436:Renal Insufficiency, Chronic D015398:Signal Transduction D015854:Up-Regulation
chronic kidney disease signaling cell signaling fibrosis obstructive nephropathy