Growth differentiation factor-15 preserves Klotho expression in acute kidney injury and kidney fibrosis

纺神星 急性肾损伤 纤维化 医学 肾脏发育 内科学 内分泌学 生长因子 病理 生物 基因 遗传学 受体 胚胎干细胞
作者
Lara Valiño‐Rivas,Leticia Cuarental,Maria I. Ceballos,Aránzazu Pintor‐Chocano,María Vanessa Pérez-Gómez,Ana B. Sanz,Alberto Ortíz,María Dolores Sánchez-Niño
出处
期刊:Kidney International [Elsevier BV]
卷期号:101 (6): 1200-1215 被引量:51
标识
DOI:10.1016/j.kint.2022.02.028
摘要

Growth differentiation factor-15 (GDF15) is a member of the GDF subfamily with potential kidney protective functions. Here, we explored the impact of GDF15 on the expression of the kidney protective factor Klotho in models of acute kidney injury and kidney fibrosis in mice. GDF15 was the most upregulated GDF family gene in experimental toxic acute kidney injury and in kidney fibrosis transcriptomics. GDF15 function was explored in toxic acute kidney injury in genetically modified mice and following treatment with GDF15. Gdf15-deficient mice developed more severe toxic acute kidney injury (folic acid or cisplatin) while GDF15 overexpression or GDF15 administration were protective. Kidney expression of Klotho was more severely depressed in Gdf15-deficient mice and was preserved by GDF15 overexpression or GDF15 treatment. Moreover, increased plasma calcitriol levels inversely correlated with kidney Klotho across models with diverse levels of GDF15 availability. Kidney fibrosis induced by unilateral ureteral obstruction was more severe in Gdf15-deficient mice while GDF15 overexpression decreased kidney injury and preserved Klotho expression. GDF15 increased Klotho expression in vivo in healthy mice, in cultured tubular cells, and prevented Klotho downregulation by inflammatory factors in tubular cells by preventing transcription factor NF-ĸB activation. Thus, spontaneous increased kidney expression of endogenous GDF15 is not enough to prevent kidney injury, but further increments in GDF15 are kidney protecting and preserve expression of the kidney protective factor Klotho within the kidney in acute and chronic settings.
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