Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease.
Rhein is an anthraquinone compound isolated from the medicinal plant rhubarb and mainly used in the clinical treatment of diabetic nephropathy. Rhein exhibits various renoprotective functions, but the underlying mechanisms are not fully determined. However, its renoprotective properties recapitulate the role of Klotho, a renal-specific antiaging protein critical for maintaining kidney homeostasis. Here we explored the connections between rhein renoprotection and Klotho in a mouse model of adenine-induced chronic kidney disease. In addition to being an impressive Klotho upregulator, rhein remarkably reversed renal Klotho deficiency in adenine-treated mice. This effect was associated with significant improvement in disturbed serum biochemistry, profibrogenic protein expression, and kidney and bone damage. Further investigation of the molecular basis of Klotho loss revealed that these kidneys displayed marked inductions of DNA methyltransferase DNMT1/DNMT3a and Klotho promoter hypermethylation, whereas rhein treatment effectively corrected these alterations. The renal protective effects of rhein were largely abolished when Klotho was knocked-down by RNA interferences, suggesting that rhein reversal of Klotho deficiency is essential for its renoprotective actions. Thus, our study clarifies how rhein regulation of Klotho expression contributes to its renoprotection and brings new insights into Klotho-targeted strategy for the treatment of kidney diseases of various etiologies.
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; The Key Lab of Jiangsu Molecular Medicine, Nanjing University School of Medicine, Nanjing, China; Division of Nephrology, Jinling Hospital, Southern Medical University, Nanjing, China.
Qin
Q
Zhang
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Lin
L
Liu
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Wenjun
W
Lin
The Key Lab of Jiangsu Molecular Medicine, Nanjing University School of Medicine, Nanjing, China.
Shasha
S
Yin
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Aiping
A
Duan
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; Division of Nephrology, Jinling Hospital, Southern Medical University, Nanjing, China. Electronic address: liuzhihong@nju.edu.cn.
Zhihong
Z
Liu
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; The Key Lab of Jiangsu Molecular Medicine, Nanjing University School of Medicine, Nanjing, China. Electronic address: wangsencao@nju.edu.cn.
Wangsen
W
Cao
D000225:Adenine / Q000633:toxicity; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005269:Femur; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics*; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010024:Osteoporosis / Q000209:etiology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D012250:Rheum / Q000737:chemistry; D015854:Up-Regulation
D000880:Anthraquinones; C000715535:Dnmt3a protein, mouse; D004791:Enzyme Inhibitors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619381:Dnmt1 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins; D000225:Adenine; C020491:rhein
CKD; DNA methylation; Klotho; epigenetics; rhein