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Abstract: FR-PO084

AICAR, an AMPK Activator, Protects Against Cisplatin-Induced AKI Through JAK/STAT/SOCS Pathway

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Bodokhsuren, Tsogbadrakh Bodokhsuren, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Lee, Jinho, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Yun, Sohyun, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Ahn, Curie, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Oh, Kook-Hwan, Seoul National University Hospital, Seoul, Korea (the Republic of)

Group or Team Name

  • Division of Nephrology, Department of Internal Medicine, Seoul National University
Background

Cisplatin causes acute kidney injury (AKI) through proximal tubular injury. We investigated protective effect of the adenosine monophosphate protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) against cisplatin induced AKI. We investigated whether AMP-kinase activator AICAR ameliorates cisplatin induced AKI and through JAK/STAT/SOCS pathway.

Methods

Male Sprague-Dawley rats were randomly divided into four groups: control, AICAR, cisplatin and cisplatin + AICAR groups. On day 1, SD rats were injected with single dose of cisplatin (7 mg/kg, i.p.). From day 1 to 5, AICAR was administered to rats at 100mg/kg i.p. daily. Blood urea nitrogen (BUN) and the serum creatinine were measured. The kidneys were harvested on the day 5. Renal damage was analyzed in sections stained with Hemotoxylin and Eosin (H&E). Renal tissues were also examined for immunohistochemistry and western blot for p-AMPK, KIM1, cleaved caspase 3 and JAK/STAT/SOCS. For in vitro studies, NRK-52E normal rat kidney cells were treated with cisplatin and/or AICAR. By western blot, we also confirmed the expressions of p-AMPK and JAK/STAT/SOCS pathway in NRK-52E cells.

Results

A single injection of cisplatin caused marked increase of the serum creatinine and BUN levels on day 5. Peak BUN and serum creatinine levels were decreased by treatment with AICAR. As compared to the cisplatin group, acute tubular necrosis (ATN) score was improved in rats treated with cisplatin + AICAR. AICAR was protective against cisplatin induced acute tubular injury by up-regulating p-AMPK expression and down-regulating KIM-1 and cleaved caspase 3. JAK2/STAT1/SOCS1 pathway was down-regulated by AICAR treatment in our in vivo and in vitro study. AICAR was protective against cisplatin induced acute tubular injury by up-regulating p-AMPK expression in NRK-52E cells. Protein expression levels of JAK2/STAT1 were markedly ameliorated in NRK-52E cells by AICAR.

Conclusion

Thus, the present study demonstrates the protective effect of AICAR in cisplatin-induced ATN and shows a new renoprotective mechanism through JAK2/STAT1/SOCS1 pathway and apoptosis inhibition. This study suggests that activation of AMPK activator, AICAR might ameliorate the cisplatin induced AKI.