HL156A, an AMP-Activated Protein Kinase Activator, Inhibits Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2024-07, Vol.14 (7), p.806
• Main Authors: Seo, Sujung, Kim, Hyunho, Hwang, Jung-Taek, Kim, Jin Eop, Kim, Jisu, Jeon, Sohyun, Song, Young-Jin, Choi, Kwang-Ho, Sim, Gwangeon, Cho, Myunkyu, Yoon, Jong-Woo, Kim, Hyunsuk
• Format: Article
• Language: English
• Subjects: Adenosine kinase; ADPKD; AMP; AMP-activated protein kinase; AMPK activator; Animal models; Antibodies; Aquaporin 2; Cell proliferation; Cell viability; Collecting duct; collecting duct-specific Pkd1 KO mice; Cre recombinase; Cysts; Drug dosages; Hereditary diseases; HL156A; Kidney diseases; Kinases; Laboratories; Metformin; Mutation; Phosphorylation; Polycystic kidney; Proteins; Recovery of function; Renal function; RNA-directed DNA polymerase; Telomerase reverse transcriptase
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14070806

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder. While metformin has demonstrated the ability to inhibit cyst growth in animal models of ADPKD via activation of adenosine monophosphate-activated protein kinase (AMPK), its effectiveness in humans is limited due to its low potency. This study explored the impact of HL156A, a new and more potent AMPK activator, in a mouse model of ADPKD. To investigate whether HL156A inhibits the proliferation of renal cyst cells in ADPKD in vitro, exogenous human telomerase reverse transcriptase (hTERT)-immortalized renal cyst cells from ADPKD patients were treated with HL156A, and an MTT (dimethylthiazol-diphenyltetrazolium bromide) assay was performed. To assess the cyst-inhibitory effect of HL156A in vivo, we generated conditional knockout (KO) mice with aquaporin 2 (AQP2)-Cre, which selectively expresses Cre recombinase in the collecting duct. The effectiveness of HL156A in inhibiting cyst growth and improving renal function was confirmed by measuring the number of cysts and blood urea nitrogen (BUN) levels in the collecting duct-specific KO mice. When cyst cells were treated with up to 20 µM of metformin or HL156A, HL156A reduced cell viability by 25% starting at a concentration of 5 µM, whereas metformin showed no effect. When AQP2-Cre male mice were crossed with female mice, and when AQP2-Cre female mice were crossed with male mice, the number of litters produced by both groups was comparable. In collecting duct-specific KO mice, HL156A was found to inhibit cyst growth, reducing both the number and size of cysts. Furthermore, it was confirmed that kidney function improved as HL156A treatment led to a reduction in elevated BUN levels. Lastly, it was observed that the increase in AMPK phosphorylation induced by HL156A decreased ERK phosphorylation and α-SMA expression. HL156A has potential as a drug that can restore kidney function in ADPKD patients by inhibiting cyst growth.