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

Acta Pharmacologica Sinica volume 44, pages 2432–2444 (2023)Cite this article

Abstract

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.

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Fig. 1: Serum TNF-α is correlated with the severity of PCOS and associated with tubular injury in PCOS.
Fig. 2: TNF-α is correlated with the severity of PCOS in primary cultured GCs.
Fig. 3: TNF-α is upregulated in PCOS mice.
Fig. 4: PCOS mediates apoptosis and inflammation in kidney, and promotes renal fibrosis.
Fig. 5: Renal TNFR1 is upregulated in PCOS promoting NF-κB signaling activation.
Fig. 6: Granulosa cell-derived conditioned medium contributes to renal tubular cell injury in vitro.
Fig. 7: Knockdown of TNF-α in granulosa cell decreases renal tubular cell injury in vitro.
Fig. 8: Knockdown of TNFR1 in HKC-8 cells attenuates granulosa cell-derived tubular cell injury in vitro.
Fig. 9: Working model.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Grant 82225010, 82070707); Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University (2019J013, 2021J001); the Presidential Foundation of Nanfang Hospital (Grant No. 2019Z006), and Guangdong Provincial Clinical Research Center for Kidney Disease (No. 2020B1111170013).

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  1. These authors contributed equally: Hui-yun Ye, Ya-li Song, Wen-ting Ye.

Authors and Affiliations

  1. Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China

    Hui-yun Ye, Wen-ting Ye, Jie-mei Li, Jin-hua Miao, Wei-wei Shen, Xiao-long Li & Li-li Zhou

  2. Center for Reproductive Medicine, Dongguan Maternal and Child Health Care Hospital, Southern Medical University, Dongguan, 523057, China

    Ya-li Song

  3. Division of Nephrology, Dongguan First Hospital of Guangdong Medical University, Dongguan, 523710, China

    Chong-xiang Xiong

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Contributions

LLZ conceived this study. LLZ and YLS participated in its design and coordination. HYY, WTY, CXX, JML, JHM, WWS and XLL conducted the experiments and contributed to data analysis and interpretation. HYY drafted the manuscript. LLZ helped to revise the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Ya-li Song or Li-li Zhou.

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Ye, Hy., Song, Yl., Ye, Wt. et al. Serum granulosa cell-derived TNF-α promotes inflammation and apoptosis of renal tubular cells and PCOS-related kidney injury through NF-κB signaling. Acta Pharmacol Sin 44, 2432–2444 (2023). https://doi.org/10.1038/s41401-023-01128-0

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