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.
Highlights
Accumulation of excess lipids in non-adipose tissues is associated with cellular dysfunction and injury (Weinberg 2006)
Our results suggest that storage of exogenous fatty acids in lipid droplets might contribute to the renoprotective effects of prolyl hydroxylases (PHDs) inhibitors (PHDi) in experimental kidney diseases (Schley et al 2019; Schley et al 2012)
Using Oil Red (OR) staining, lipid droplets were detected in individual tubular cells scattered throughout the renal cortex of both Cre− and Phd2ΔKsp mice (Fig. 1c–f), which were identified as proximal tubular cells by co-immunostaining for the sodium phosphate cotransporter (NaPi) IIa (Fig. 1g, h)
Summary
Accumulation of excess lipids in non-adipose tissues is associated with cellular dysfunction and injury (Weinberg 2006). Fatty acids (FA) are the best energy-yielding substrates producing three times more ATP than glucose. They are the preferred substrates of proximal tubular cells (Guder et al 1986; Silva 1990), which have a high energy demand for the reabsorption of solutes, mainly sodium, from the glomerular filtrate (Layton et al 2016). FA are mostly bound to albumin and enter the proximal tubular cell from the basolateral surface in linear correlation to their arterial concentration (Wirthensohn and Guder 1986). In the presence of high urinary amounts of albumin in proteinuric kidney diseases, FA can be obtained from the glomerular filtrate across the luminal surface (Bobulescu 2010; Moorhead et al 1982). FA can either be degraded by β-oxidation or can be incorporated into triacylglycerols
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