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

Abstract

The role of the hypoxia-inducible transcription factor (HIF) pathway in renal lipid metabolism is largely unknown. As HIF stabilizing prolyl hydroxylase (PHD) inhibitors are currently investigated in clinical trials for the treatment of renal anemia, we studied the effects of genetic deletion and pharmacological inhibition of PHDs on renal lipid metabolism in transgenic mice and human primary tubular epithelial cells (hPTEC). Tubular cell-specific deletion of HIF prolyl hydroxylase 2 (Phd2) increased the size of Oil Red-stained lipid droplets in mice. In hPTEC, the PHD inhibitors (PHDi) DMOG and ICA augmented lipid accumulation, which was visualized by Oil Red staining and assessed by microscopy and an infrared imaging system. PHDi-induced lipid accumulation required the exogenous availability of fatty acids and was observed in both proximal and distal hPTEC. PHDi treatment was not associated with structural features of cytotoxicity in contrast to treatment with the immunosuppressant cyclosporine A (CsA). PHDi and CsA differentially upregulated the expression of the lipid droplet-associated genes PLIN2, PLIN4 and HILPDA. Both PHDi and CsA activated AMP-activated protein kinase (AMPK) indicating the initiation of a metabolic stress response. However, only CsA triggered endoplasmic reticulum (ER) stress as determined by the increased mRNA expression of multiple ER stress markers but CsA-induced ER stress was not linked to lipid accumulation. Our data raise the possibility that PHD inhibition may protect tubular cells from toxic free fatty acids by trapping them as triacylglycerides in lipid droplets. This mechanism might contribute to the renoprotective effects of PHDi in experimental kidney diseases.

Transcription-Based Multidimensional Regulation of Fatty Acid Metabolism by HIF1α in Renal Tubules

“…Other than the well-known effect of enhancing anaerobic glycolysis, studies have illustrated that HIF promotes lipid storage in liver and clear cell renal cell carcinoma (Rankin et al, 2009;Qiu et al, 2015;Du et al, 2017). Very recently, PHD inhibition was found to increase lipid accumulation in human tubular epithelial cells, suggesting participation of HIF in tubular lipid regulation, although the concrete mechanism still needs further investigation (Schley et al, 2020). We provide evidence that HIF1α activation has inhibitory effects on tubular lipid metabolism, including FAO, leading to lipid accumulation.…”

“…The mechanisms mainly include induction of mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis, and reactive oxygen species and proinflammatory factor production (Weinberg, 2006;Bobulescu, 2010;Bhargava and Schnellmann, 2017). HIF was recently found to be linked with renal tubular lipid accumulation, although further investigations are needed to reveal the concrete mechanism (Schley et al, 2020).…”

Ferroptosis-Related Gene Signature Promotes Ovarian Cancer by Influencing Immune Infiltration and Invasion

“…Critically, we identified that a novel potential sensitive drug is dimethyloxallyl glycine (DMOG), a kind of prolyl hydroxylase inhibitor (PHI), may be able to treat invasive ovarian cancer. In terms of the association between DMOG and lipid metabolism, studies have found that DMOG can increase lipid accumulation in human primary renal tubular epithelial cells [41] and lipid absorption in macrophages [42]. erefore, DMOG may serve as a novel potential targeted drug for ovarian cancer.…”

Hypoxia response and acute lung and kidney injury: possible implications for therapy of COVID-19

“…It has been shown that lipotoxicity could contribute to the development of AKI and HIF could promote fatty acids accumulation in cells. However, in an experimental model of transgenic mice and human primary tubular epithelial cells, differing from cyclosporin treatment, the genetic deletion and pharmacological inhibition of PHDs (and thus the activation of the HIF system) did not cause cytotoxicity [ 49 ]. On the contrary, it may possibly protect tubular cells from toxic free fatty acids by trapping them as triacylglycerides in lipid droplets [ 49 ].…”