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Abstract: PO0435

Renal GPNMB Is Highly Upregulated in Rodent Models of AKI and Is Further Elevated with Pharmacological AMPK Activation

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Qi, Jenson, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Frikke-Schmidt, Henriette, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Aleman Muench, German, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Ma, Li-Jun, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Albarazanji, Kamal, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Skrypnyk, Nataliya, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Huang Devine, Zheng, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Guo, Lili, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Pocai, Alessandro, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Leonard, James, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
Background

Glycoprotein nonmetastatic melanoma B (GPNMB) is highly expressed in macrophages. GPNMB is an AMP-activated protein kinase (AMPK) up-regulated gene in whole bloods. GPNMB deficient mice fail to undergo repair and injury resolution following kidney ischemia reperfusion injury (IRI). Here we investigated GPNMB expression in the rat IRI and mouse cisplatin AKI models with or without an AMPK activator treatment. We also characterized GPNMB expression in human proximal epithelial cells, M1 and M2 macrophages.

Methods

RPTEC and HK2 cells were exposed to hypoxia for 24 h. GMCSF- or MCSF- primed human M1 or M2 macrophages were isolated from human LeukoPaks. Male SD rats were subjected to 40 min of bilateral renal ischemia. Kidneys were harvested 2 days after IRI. Male C57B mice were administered with a single injection of cisplatin. Kidneys were harvested 72 h after cisplatin injection.

Results

In human proximal epithelial HK2 and RPTEC cells, an AMPK activator treatment resulted in a dose-dependent increase of GPNMB mRNA. Significant increase of GPNMB mRNA was observed in HK2 and RPTEC cells cultured in hypoxic versus normoxic conditions. We also demonstrated that AMPK activation increased IFNγ and LPS-induced GPNMB secretion in human M2 but not M1 macrophages.

After a single oral administration of an AMPK activator in normal mice or rats, a robust induction of GPNMB mRNA in the whole blood was seen starting 3 h and lasting up to 22 h. We found that GPNMB mRNA was expressed at low levels in the kidneys of normal mice or rats. GPNMB mRNA was markedly up-regulated following IRI in the kidneys at 48 h. In a mouse cisplatin-induced AKI model, a dramatic increase of GPNMB mRNA was observed in the kidneys. Pharmacological activation of AMPK in both AKI models resulted in further increase of renal GPNMB.

Conclusion

GPNMB mRNA is highly up-regulated in the kidneys of rat IRI and mouse cisplatin AKI models and is further elevated after an AMPK activator treatment. GPNMB is a gene marker for AMPK activation in tubular epithelial cells, M2 macrophages, and whole bloods. Our results support that GPNMB could modulate macrophages polarization which may be involved in inflammation and immune response, contributing to injury and repair post AKI.

Funding

  • Commercial Support