Kidney Week

Abstract: TH-PO407

A Novel Kidney-Selective AMPK Activator Slows Renal Cystic Disease and Fibrosis in PKD Mice

Session Information

• Genetic Diseases: Cystic - Therapeutic Investigations and Prognosis
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Zhang, Yan, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Yan Zhang,

• Daniel, Emily A., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Emily A. Daniel,

• Dai, Yuqiao, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Yuqiao Dai,

• Reif, Gail, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Gail Reif,

• Batchelor, Ken W., Pano Therapeutics, Inc, Haleiwa, Hawaii, United States

Ken W. Batchelor,

• Wallace, Darren P., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Darren P. Wallace,

Background

ADPKD is characterized by progressive enlargement of fluid-filled cysts, leading to inflammation and fibrosis, and a decline in kidney function. Metformin, the only FDA-approved AMPK activator and most commonly used drug for the treatment of type 2 diabetes, reduced mTOR-mediated cell proliferation and CFTR-mediated ion transport in Pkd1 mutant cells and inhibited cyst growth of rapid PKD models. However, metformin-associated lactic acidosis, a potentially lethal side effect, raises concerns about its application for long-term treatment of ADPKD. Metformin is a biguanide that requires an organic cation transporter (OCT) to be taken up by cells and is transported into the kidneys via OCT2; however, it is not a substract for OCTN1/2 and is eliminated in urine. In collaboration with Pano Therapeutics, we tested biguanides with improved potency for AMPK, OCT2, and OCTN1/2. PAN1021 was 38× more potent for OCT2 and >100× more potent of OCTN1/2 than metformin, thus reducing renal elimination. Previously, PAN1021 decreased mTOR signaling, proliferation, anion secretion, and in vitro cyst formation of human ADPKD cells. Here, we compared effects of PAN1021 and metformin on cyst disease, inflammation, and fibrosis in an orthologous PKD mouse model.

Methods

PAN1021 (100mg/kg) or metformin (300mg/kg) was delivered to Pkd1^RC/RC:Pkd2^+/- mice, an early onset PKD model, by daily gavage from 5 to 20 wk. Mice were killed 3 h after the last treatment, and blood and kidneys were collected for analysis.

Results

PAN1021 had no effect on body weight, appearance, or behavior of the PKD mice, indicating that the drug was safe, and it caused a significant decrease in kidney weight (%body weight; KW/BW). By contrast, the metformin response was variable and half of the mice showed an increase in KW/BW. Both drugs reduced renal fibrosis and BUN. PAN1021 reduced P-S6/S6, a component of mTOR signaling, and PCNA, a proliferation marker. It potently reduced TNF-α and F480, inflammation markers, and α-SMA and collagen 1A1, fibrosis markers, and restored the levels of PPARα, a regulator of fatty acid oxidation.

Conclusion

A novel kidney-selective AMPK activator PAN1021 inhibits renal mTOR, cell proliferation, cyst growth, tissue inflammation, and fibrosis in PKD mice. PAN1021 has an OCT profile anticipated to reduce the risk of lactic acidosis in ADPKD patients.

Funding

• NIDDK Support