PPARγ agonist alleviates calcium oxalate nephrolithiasis by regulating mitochondrial dynamics in renal tubular epithelial cell

• Published in: PloS one 2024-09, Vol.19 (9), p.e0310947
• Main Authors: Liu, Junfa, Liu, Xingyang, Guo, Lizhe, Liu, Xiongfei, Gao, Qian, Wang, E, Dong, Zhitao
• Format: Article
• Language: English
• Subjects: Agonists; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Bioaccumulation; Biology and Life Sciences; Calcium; Calcium (blood); Calcium (mitochondrial); Calcium oxalate; Calcium Oxalate - metabolism; Calcium signalling; Calculi; Cell culture; Cell Line; Critical components; Crystallization; Crystals; Disease; Disease Models, Animal; Drinking water; Dynamics; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Ethylene glycol; Fibrosis; Fission; Gene expression; Homeostasis; Humans; In vivo methods and tests; Inflammation; Injury analysis; Kidney stones; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Laboratory animals; Lithiasis; Male; Medicine and Health Sciences; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Dynamics - drug effects; Nephrolithiasis; Nephrolithiasis - drug therapy; Nephrolithiasis - metabolism; Nephrolithiasis - pathology; Oxalic acid; Oxidative stress; Oxidative Stress - drug effects; Peroxisome proliferator-activated receptors; Physical Sciences; PPAR gamma - agonists; PPAR gamma - metabolism; Quality control; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Renal function; Research and Analysis Methods; Ribonucleic acid; RNA
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0310947

Kidney stone formation is a common disease that causes a significant threat to human health. The crystallization mechanism of calcium oxalate, the most common type of kidney stone, has been extensively researched, yet the damaging effects and mechanisms of calcium oxalate crystals on renal tubular epithelial cells remain incompletely elucidated. Regulated mitochondrial dynamics is essential for eukaryotic cells, but its role in the occurrence and progression of calcium oxalate (CaOx) nephrolithiasis is not yet understood. An animal model of calcium oxalate-related nephrolithiasis was established in adult male Sprague‒Dawley (SD) rats by continuously administering drinking water containing 1% ethylene glycol for 28 days. The impact of calcium oxalate crystals on mitochondrial dynamics and apoptosis in renal tubular epithelial cells was investigated using HK2 cells in vitro. Blood samples and bilateral kidney tissues were collected for histopathological evaluation and processed for tissue injury, inflammation, fibrosis, oxidative stress detection, and mitochondrial dynamics parameter analysis. Calcium oxalate crystals caused higher levels of mitochondrial fission and apoptosis in renal tubular epithelial cells both in vivo and in vitro. Administration of a PPARγ agonist significantly alleviated mitochondrial fission and apoptosis in renal tubular epithelial cells, and improved renal function, accompanied by reduced levels of oxidative stress, increased antioxidant enzyme expression, alleviation of inflammation, and reduced fibrosis in vivo. Our results indicated that increased mitochondrial fission in renal tubular epithelial cells is a critical component of kidney injury caused by calcium oxalate stones, leading to the accumulation of reactive oxygen species within the tissue and the subsequent initiation of apoptosis. Regulating mitochondrial dynamics represents a promising approach for calcium oxalate nephrolithiasis.