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

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.

Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis

“…Excessive lipid accumulation and impaired FAO have been repeatedly observed in several animal models of acute and chronic renal injury, as well as in human patients (10,11,13,47,48). Increased lipid accumulation induces cellular lipotoxicity, contributing to fibrosis development (11).…”

Inhibition of oxygen-sensing prolyl hydroxylases increases lipid accumulation in human primary tubular epithelial cells without inducing ER stress

“…In human kidney biopsies with CKD and in mouse models of kidney fibrosis, enzymes and regulators of FA oxidation were found to be downregulated (Kang et al 2015). However, in proximal tubular epithelial cells isolated from proteinuric human patients and in differentiated proximal tubules isolated from fibrotic mouse kidneys, the FA oxidation was instead upregulated (Bataille et al 2018;Rudnicki et al 2007).…”

Metabolic Reprogramming and Renal Fibrosis

“…Since the "lipid nephrotoxicity hypothesis" was first proposed in 1982 (56), there has been increasing evidence that supports the close relationship between altered lipid metabolism and kidney disease (57). In particular, studies of patients and animal models of renal interstitial fibrosis reported that the key enzymes regulating FAO had reduced function, and that this led to increased intracellular lipid deposition, thus confirming that reduced FAO activity is a strong determinant of renal fibrosis (58)(59)(60). For example, mice fed a high-fat diet (HFD) accumulated lipids in the kidneys, and this led to structural damage of tubular epithelial cells, inflammation, and fibrosis (61,62).…”