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J Am Soc Nephrol. 2018 Apr;29(4):1223-1237. doi: 10.1681/ASN.2017070802. Epub 2018 Feb 12.

Impairment of PPARα and the Fatty Acid Oxidation Pathway Aggravates Renal Fibrosis during Aging.

Author information

1
Molecular Inflammation Research Center for Aging Intervention and.
2
Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
3
Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea.
4
Department of Pathology, Ilsin Christian Hospital, Busan, Republic of Korea.
5
Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea; and.
6
Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
7
Molecular Inflammation Research Center for Aging Intervention and hyjung@pusan.ac.kr.

Abstract

Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator-activated receptor α (PPARα) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPARα and the FAO pathway-associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPARα protein expression associated with increased expression of PPARα-targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPARα expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF-β-induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPARα-/- mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPARα signaling during aging aggravates renal fibrosis development, and targeting PPARα is useful for preventing age-associated CKD.

KEYWORDS:

Aging; Fatty acid oxidation; PPARα; fibrosis; miR21

PMID:
29440279
PMCID:
PMC5875952
DOI:
10.1681/ASN.2017070802
[Indexed for MEDLINE]
Free PMC Article

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