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.

Abstract

BACKGROUND:

Renal fibrosis is characterized by excessive production and deposition of extracellular matrix (ECM), which leads to progressive renal failure. Adenosine-monophosphate-activated protein kinase (AMPK) is a highly conserved kinase that plays a key role in Smad-3 signaling. Here, we examined the effect of a novel AMPK activator, HL156A, on the inhibition of renal fibrosis in in vivo and in vitro models.

METHODS:

Unilateral ureteral obstruction (UUO) was induced in male Wistar rats. Rats with UUO were administered HL156A (20mg/kg/day), and then the kidneys were harvested 10 days after ligation for further analysis.

RESULTS:

In the rat UUO model, HL156A attenuated ECM protein deposition. After HL156A treatment, expressions of TGF-β1, p-Smad3, α-SMA, fibronectin, and type IV collagen were suppressed, and E-cadherin expression was up-regulated. In the in vitro experiment, NRK52E cells were treated with HL156A before TGF-β1 stimulation. The inhibitory effects of HL156A upon the signaling pathways and markers of the epithelial-to-mesenchymal transition (EMT) were analyzed. In TGF-β1-treated NRK-52E cells, HL156A co-treatment inhibited the TGF-β1-induced Smad3 signaling pathway and EMT markers.

CONCLUSION:

Taken together, the above findings suggest that HL156A, a novel AMPK activator, ameliorates renal fibrosis in vivo and in vitro.

• Authors: Bodokhsuren Tsogbadrakh, Kyung Don Ju, Jinho Lee, Miyeun Han, Junga Koh, Yeonsil Yu, Hajeong Lee, Kyung-Sang Yu, Yun Kyu Oh, Hyo Jin Kim, Curie Ahn, Kook-Hwan Oh
• Journal: PloS one (PLoS One) Vol. 13 Issue 8 Pg. e0201692 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 30161162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Guanidines
• HL156A
• Pyrrolidines
• Smad3 Protein
• Transforming Growth Factor beta1
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Line
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects)
• Fibrosis
• Guanidines (pharmacology, therapeutic use)
• Kidney (drug effects, metabolism, pathology)
• Pyrrolidines (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Smad3 Protein (metabolism)
• Time Factors
• Transforming Growth Factor beta1 (metabolism)
• Ureteral Obstruction (pathology)