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Abstract: SA-PO595

Renal Epithelial Cells Reprogram Metabolism to Adapt to Sepsis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Manrique-Caballero, Carlos L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Emlet, David R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Frank, Alicia, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Marrow, Abigail E., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Kellum, John A., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Gomez Danies, Hernando, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Adaptive metabolic reprogramming may play a key role in the development of sepsis induced acute kidney injury (AKI). Like monocytes, renal tissue shifts metabolism toward glycolysis early after cecal ligation and puncture. In monocytes, this shift is driven by the hypoxia inducible factor (HIF-1a) though expression of pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase kinase (PDHK), whereas return to oxidative phosphorylation (OXPHOS) is driven by the activation of Sirtuin 1 (Sirt1). We hypothesized that human kidney 2 cells (HK2) follow the same biphasic reprogramming as an adaptive mechanism to sepsis.


HK2 were cultured in serum containing media and plated in XF24 microplates and 6-well plates for Seahorse and immunoblotting (WB) respectively at 21% O2. Cells were treated with vehicle or sepsis mix (SM=LPS+HMGB1). We measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) as surrogates of glycolysis and OXPHOS, respectively at 3 and 24 hours after treatment. HIF-1a, PDHK, Sirt1 and b-Actin were identified by WB at 3, 6, and 24h.


SM induced a decline in ECAR and an increase in OCR at 24h (Fig 1), suggesting that utilization of glycolysis decreases, and utilization of OXPHOS increases by 24h of SM. SM induced an increase in HIF-1α levels at 3h, with a late decrease by 24h. Protein levels of the downstream HIF-1α target, PDHK also increased from 3 to 6h, followed by a similar decline by 24h. SM induced a delayed increase in Sirt1 by 24h, with an early suppression at 3h (Fig 2).


Our study shows that in response to SM, HK2 cells shift metabolism by decreasing the use of glycolysis and increasing the use of OXPHOS by 24h. Increased expression of drivers and mediators of glycolysis early (3h) after SM, followed by a late (24h) decline in glycolysis concomitant with increased expression of drivers of OXPHOS, suggests a biphasic HK2 response to inflammation, reminiscent of that of monocytes.

Fig 1. Change in glycolysis and OXPHOS from 3 to 24h after exposure to SM
Fig 2. Protein expression of drivers of glycolysis and OXPHOS in HK2 cells after SM


  • Other NIH Support