Serum granulosa cell-derived TNF-α promotes inflammation and apoptosis of renal tubular cells and PCOS-related kidney injury through NF-κB signaling

• Published in: Acta pharmacologica Sinica Vol. 44; no. 12; pp. 2432 - 2444
• Main Authors: Ye, Hui-yun, Song, Ya-li, Ye, Wen-ting, Xiong, Chong-xiang, Li, Jie-mei, Miao, Jin-hua, Shen, Wei-wei, Li, Xiao-long, Zhou, Li-li
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.12.2023; Nature Publishing Group
• Subjects: Apoptosis; Biomedical and Life Sciences; Biomedicine; Cell culture; Cell injury; Dihydrotestosterone; Epithelial cells; Fibrosis; Follicle-stimulating hormone; Granulosa cells; Immunology; Inflammation; Internal Medicine; Kidney diseases; Kidneys; Luteinizing hormone; Medical Microbiology; NF-κB protein; Ovaries; Pharmacology/Toxicology; Polycystic ovary syndrome; Proteinuria; Testosterone; Tumor cells; Tumor necrosis factor receptor 1; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vaccine; apoptosis; TNF-α; kidney injury; inflammation; polycystic ovary syndrome; TNFR1
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-023-01128-0

Polycystic ovary syndrome (PCOS) is a disorder with endocrinal and metabolic problems in reproductive aged women. Evidence shows that PCOS is in a high prone trend to develop kidney diseases. In this study, we investigated the mediators responsible for PCOS-related kidney injury. We found that tumor necrosis factor (TNF-α) levels were significantly increased in serum and primary cultured granulosa cells (GCs) from PCOS patients. Serum TNF-α levels were positively correlated with serum testosterone and luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, suggesting its positive role in the severity of PCOS. Serum TNF-α levels were also positively correlated with the levels of urinary KapU, LamU, α1‐MU and β2‐MU, the markers for renal tubular cell-derived proteinuria. We established a PCOS mouse model by resection of the right kidney, followed by daily administration of dihydrotestosterone (DHT, 27.5 μg, i.p.) from D7 for 90 days. We found that TNF-α levels were significantly increased in the ovary and serum of the mice, accompanied by increased renal tubular cell apoptosis, inflammation and fibrosis in kidneys. Furthermore, the receptor of TNF-α, tumor necrosis factor receptor 1 (TNFR1), was significantly upregulated in renal tubular cells. We treated human ovarian granulosa-like tumor cells (KGN) with DHT (1 μg/ml) in vitro, the conditioned medium derived from the granulosa cell culture greatly accelerated apoptotic injury in human proximal tubular epithelial cells (HKC-8), which was blocked after knockdown of TNF-α in KGN cells. Furthermore, knockdown of TNFR1 in renal tubular epithelial cells greatly ameliorated cell injury induced by granulosa cell-derived conditioned medium. These results suggest that serum TNF-α plays a key role in mediating inflammation and apoptosis in renal tubular cells associated with PCOS-related kidney injury.