title: Atrasentan increased the expression of klotho by mediating miR-199b-5p and prevented renal tubular injury in diabetic nephropathy.
abstract: Atrasentan is a promising therapy for treating diabetic nephropathy (DN). Here we evaluated whether atrasentan down-regulated the miR-199b-5p expression, thereby increasing klotho and preventing renal tubular injury in DN. One-hundred patients with type 2 diabetes mellitus (T2DM) and 40 healthy subjects were included. A DN mice model was established by an injection of streptozotocin (STZ). Human renal proximal tubular epithelial HK-2 cells were exposed to high glucose (20 mmol/L). Treated the mice and HK-2 cells with atrasentan, and we then investigated whether and how miR-199b-5p and Klotho were involved in preventing renal tubular injury in DN. In patients, the serum miR-199b-5p level increased and the klotho concentration decreased in accordance with elevated albuminuria. Atrasentan down-regulated miR-199b-5p and up-regulated klotho of the DN mice and HK-2 cells exposed to high glucose. High glucose promoted the binding of histone H3 to the miR-199b-5p promoter, and atrasentan canceled this effect. MiR-199b-5p targeted the 3' UTR of klotho. Overexpression of miR-199b-5p canceled the effects of atrasentan on klotho expression and apoptosis of renal tubular cells in both in vivo and in vitro. The increased serum klotho, mediated by miR-199b-5p, is a possible mechanism by which atrasentan prevents renal tubular injury in DN.
authors.affiliation: Medical Center of the Graduate School, Nanchang University, Nanchang 330000, China.|Department of Nephrology, People's Hospital of Xinyu City, Xinyu 338000, China.
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Kang
authors.affiliation: Department of Nephrology, Second Affiliated Hospital, Nanchang University, Nanchang 330006 China.
authors.forename: Gao-Si
authors.initials: GS
authors.lastname: Xu
mesh_terms: D020413:3' Untranslated Regions; D000419:Albuminuria; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D000077868:Atrasentan; D015415:Biomarkers; D002460:Cell Line; D019175:DNA Methylation; D003928:Diabetic Nephropathies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011759:Pyrrolidines / Q000494:pharmacology*; D034622:RNA Interference
chemical_list: D020413:3' Untranslated Regions; D000975:Antioxidants; D015415:Biomarkers; D035683:MicroRNAs; D011759:Pyrrolidines; C531408:mirn199 microRNA, human; D005966:Glucuronidase; D000090265:Klotho Proteins; D000077868:Atrasentan
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