Clusterin deficiency induces lipid accumulation and tissue damage in kidney.

Abstract

Clusterin is a secretory glycoprotein that is involved in multiple physiopathological processes, including lipid metabolism. Previous studies have shown that clusterin prevents hepatic lipid accumulation via suppression of sterol regulatory element-binding protein (SREBP) 1. In this study, we examined the role of clusterin in renal lipid accumulation in clusterin-knockout mice and NRK52e tubular epithelial cells. Clusterin deficiency increased the expression of SREBP1 and its target genes and decreased malonyl-CoA decarboxylase protein levels in the kidney. Expression of the endocytic receptor, megalin, and scavenger receptor class A was increased in clusterin-deficient mice. Functional analysis of lipid metabolism also revealed that lipid uptake and triglyceride synthesis were increased and fatty acid oxidation was reduced, leading to increased lipid accumulation in clusterin-deficient mice. These phenomena were accompanied by mesangial expansion, fibrosis and increased urinary protein-to-creatinine ratio. High-fat feeding aggravated these clusterin deficiency-induced pathological changes. Clusterin knockdown in NRK52e cells increased lipogenic gene expression and lipid levels, whereas overexpression of clusterin by treatment with adenovirus or recombinant clusterin protein suppressed lipogenic gene expression and lipid levels. Transforming growth factor-beta 1 (TGFB1) expression increased in the kidney of clusterin-deficient mice and suppression of TGFB1 in NRK52e cells suppressed lipid accumulation. These results suggest that clusterin deficiency induces renal lipid accumulation by dysregulating the expression of lipid metabolism-related factors and TGFB1, thereby leading to chronic kidney disease. Hence, clusterin may serve as a therapeutic target for lipid-induced chronic kidney disease.

• Authors: Jung-Yoon Heo, Ji-Eun Kim, Yongwook Dan, Yong-Woon Kim, Jong-Yeon Kim, Kyu Hyang Cho, Young Kyung Bae, Seung-Soon Im, Kwang-Hyeon Liu, In-Hwan Song, Jae-Ryong Kim, In-Kyu Lee, So-Young Park
• Journal: The Journal of endocrinology (J Endocrinol) Vol. 237 Issue 2 Pg. 175-191 (05 2018) ISSN: 1479-6805 [Electronic] England
• PMID: 29563234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Society for Endocrinology.

Chemical References

• Clu protein, mouse
• Clusterin
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1

Topics

• Animals
• Cells, Cultured
• Clusterin (genetics)
• Fibrosis (genetics)
• Gene Deletion
• Kidney (metabolism, pathology)
• Lipid Metabolism (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Rats
• Renal Insufficiency, Chronic (genetics, metabolism, pathology)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Up-Regulation (genetics)