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Cell Physiol Biochem. 2018;47(4):1338-1351. doi: 10.1159/000490819. Epub 2018 Jun 19.

Increased Fatty Acid Oxidation in Differentiated Proximal Tubular Cells Surviving a Reversible Episode of Acute Kidney Injury.

Author information

1
Sorbonne Universités, INSERM UMR S 1155, Hôpital Tenon, Paris, France.
2
Department of Anesthesiology and Critical Care Medicine, Lariboisiere Hospital, University Paris 7 Diderot, U942, Inserm, Paris, France.
3
APHP, Hôpital Tenon, Urgences Néphrologiques et Transplantation Rénale, 4 rue de la Chine, Paris, France.
4
Sorbonne Universités, UPMC Université Paris 06, Inserm, UMS Omique, Plateforme P3S, Paris, France.
5
Sorbonne Universités, UPMC Université Paris 06, CNRS, Institut de Biologie Paris-Seine (IBPS), Evolution Paris Seine, Paris, France.

Abstract

BACKGROUND/AIMS:

Fatty acid oxidation (FAO), the main source of energy produced by tubular epithelial cells in the kidney, was found to be defective in tubulo-interstitial samples dissected out in kidney biopsies from patients with chronic kidney disease (CKD). Experimental data indicated that this decrease was a strong determinant of renal fibrogenesis, hence a focus for therapeutic interventions. Nevertheless, whether persistently differentiated renal tubules, surviving in a pro-fibrotic environment, also suffer from a decrease in FAO, is currently unknown.

METHODS:

To address this question, we isolated proximal tubules captured ex vivo on the basis of the expression of an intact brush border antigen (Prominin-1) in C57BL6/J mice subjected to a controlled, two-hit model of renal fibrosis (reversible ischemic acute kidney injury (AKI) or sham surgery, followed by angiotensin 2 administration). A transcriptomic high throughput sequencing was performed on total mRNA from these cells, and on whole kidneys.

RESULTS:

In contrast to mice subjected to sham surgery, mice with a history of AKI displayed histologically more renal fibrosis when exposed to angiotensin 2. High throughput RNA sequencing, principal component analysis and clustering showed marked consistency within experimental groups. As expected, FAO transcripts were decreased in whole fibrotic kidneys. Surprisingly, however, up- rather than down-regulation of metabolic pathways (oxidative phosphorylation, fatty acid metabolism, glycolysis, and PPAR signalling pathway) was a hallmark of the differentiated tubules captured from fibrotic kidneys. Immunofluorescence co-staining analysis confirmed that the expression of FAO enzymes was dependent of tubular trophicity.

CONCLUSIONS:

These data suggest that in differentiated proximal tubules energetic hyperactivity is promoted concurrently with organ fibrogenesis.

KEYWORDS:

Acute Kidney Injury; Chronic Kidney Disease; Epithelium; Fatty Acid Oxidation; Fibrosis

PMID:
29929186
DOI:
10.1159/000490819
[Indexed for MEDLINE]
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