Kidney Week

Abstract: TH-PO456

Glucagon-Like Peptide 1 Receptor Agonist (GLP-1 RA) Delays Cyst Growth in ADPKD

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Wu, Jiao, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Jiao Wu

• Cheng, Shasha, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Shasha Cheng, PhD

• Zhang, Yingying, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Yingying Zhang, MD, PhD

• Li, Xiaoyan, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xiaoyan Li, MD, PhD

• Zhou, Xia, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xia Zhou, MD, PhD

• Li, Xiaogang, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xiaogang Li, PhD

Background

ADPKD is the most frequent genetic cause of chronic kidney disease (CKD), accounting for 6-10 % of patients on dialysis in the United States. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of drugs utilized to treat type 2 diabetes mellitus and obesity due to its profound glycemic control effect and weight lowering. In this study, we tested the effect of one of the most popular GLP-1RA, Semaglutide, and the underlying mechanisms on the progression of ADPKD.

Methods

To determine the effect of GLP-1RA in ADPKD, we treated Pkd1^flox/flox:Pkhd1-Cre mice and Pkd1^RC/RC mice with Semaglutide (10 ug/kg) via daily intraperitoneal injection. Kidneys were collected from Pkd1^flox/flox:Pkhd1-Cre mice at PN25 and from Pkd1^RC/RC mice at PN91. Kidneys and renal tubular cells treated with Semaglutide were analyzed by H&E staining, WB, qRT-PCR, as well as immunofluorescence, immunohistochemistry, and TUNEL staining. Additionally, we utilized transmission electron microscopy to identify mitochondrial changes in Pkd1 mutant cells and kidneys.

Results

We found that the expression of GLP-1R was decreased in Pkd1 mutant renal epithelial cells and kidneys. Treatment with Semaglutide (10ug/kg) delayed cyst growth as seen by decreased cystic index, kidney weight (KW)/body weight (BW) ratios, blood urea nitrogen (BUN) levels, cyst lining epithelial cell proliferation, and increased cyst lining epithelial cell apoptosis in Pkd1 mutant mice (all p < 0.05). Treatment with Semaglutide could reduce total kidney volumes in living Pkd1^RC/RC mice as examined by ultrosoud, as well as decrease the recruitment of macrophages and the expression of fibrotic markers, including fibronectin and a-SMA, resulting in a decrease of interstitial fibrosis in Pkd1 mutant kidneys as examined by picrosirius red and a-SMA staining. Notably, we found that treatment with Semaglutide 1) decreased glucose uptake, ATP generation and glycolysis characterized by a decrease of the expression of the key glycolytic enzymes, and 2) normalized the structure of mitochondria and the expression of the genes involved in mitochondrial metabolism, in Pkd1 mutant renal epithelial cells and kidneys.

Conclusion

This study highlights a role of downregulation of GLP-1R in abnormal glycolysis and mitochondrial metabolism in Pkd1 mutant kidneys and suggests that GLP-1RA therapy may be a novel therapeutic strategy for ADPKD.

Funding

• NIDDK Support