Renal protective effects of adenosine monophosphate protein kinase (AMPK) activators in renal fibrosis and acute kidney injury model

Abstract

Adenosine monophosphate protein kinase (AMPK)는 중요한 세포 에너지 센서이다. AMPK는 전신 수준에서 신진 대사 에너지 균형을 조절한다. AMPK 활성화가 미치는 영향은 당 및 지질대사, 사이토카인 생성 및 염증 조절, 그리고 세포 증식과 세포사멸에 이르러 그 범위가 방대하다. 본 연구자는 대표적 AMPK 활성제인 HL156A가 생체 내, 생체 밖 모델에서 신장 섬유화증에 억제 효과가 있는지 연구하였다. 또한 또 다른 AMPK 활성제인 AMP-kinase activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) 가 cisplatin 에 의한 급성 신손상 설치류 모델에서 보호효과가 있는지 여부를 연구 하였다. 본 연구자는 HL156A, metformin, AICAR 처리 시 AMPK 활성증가 정도를 비교 하였고, 이중 HL165A 가 가장 강력한 AMPK 활성제임을 발견 하였다. 본 연구는 AMPK 활성제가 신장 섬유증과 급성 신손상에 보호효과가 있음을 입증 하였다. 본 연구 결과 중 일부를 다음 논문에 게재 하였다:  Tsogbadrakh, B., et al. (2018). "HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model." PLoS One 13(8): e0201692.  Tsogbadrakh, B., et al. (2019). "AICAR, an AMPK activator, protects against cisplatin-induced acute kidney injury through the JAK/STAT/SOCS pathway." Biochem Biophys Res Commun 509(3): 680-686.

Adenosine monophosphate protein kinase (AMPK) is a crucial cellular energy sensor. AMPK regulates metabolic energy balance at the whole body level. AMPK activation effect is diverse and include glucose and lipid metabolism, cytokine production and inflammation regulation, and cell proliferation and apoptosis. Here, the effects of a novel AMPK activator HL156A, on the inhibition of renal fibrosis in in vivo and in vitro models were examined. Also, it was investigated whether the AMP-kinase activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) protects against cisplatin induced acute kidney injury. The AMPK-activator activities of AICAR, metformin, and HL156A were compared in a rodent renal tubular epithelial cell line. Among the three AMPK activator substances, AMPK activation was the most potent in the presence of the HL156A molecule. Taken together, AMPK activators ameliorated renal fibrosis and acute kidney injury. Parts of the results in this thesis have been published in the following papers:  Tsogbadrakh, B., et al. (2018). "HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model." PLoS One 13(8): e0201692.  Tsogbadrakh, B., et al. (2019). "AICAR, an AMPK activator, protects against cisplatin-induced acute kidney injury through the JAK/STAT/SOCS pathway." Biochem Biophys Res Commun 509(3): 680-686.