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PRDM16 deficiency promotes podocyte injury by impairing insulin receptor signaling

Cell Death & Differentiation volume 32, pages 1536–1554 (2025)Cite this article

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Abstract

Impaired glucose uptake regulated by suppressed insulin receptor signaling is a key driving force of podocytopathies. The identification of potential therapeutic targets that mediate podocyte insulin receptor signaling holds significant clinical importance. Here, we observed a substantial reduction in PR domain-containing 16 (PRDM16) expression within damaged podocytes in both humans and mice. Podocyte-specific Prdm16 deletion aggravated podocyte injury, albuminuria, and glomerulosclerosis in diabetic nephropathy (DN) mice. Conversely, exogenous PRDM16 delivered by lentivirus mitigated these pathological changes in DN mice and adriamycin (ADR) nephropathy mice. Furthermore, we demonstrated that loss of PRDM16 blocked glucose uptake of podocytes by inhibiting insulin receptor signaling. Mechanistically, PRDM16 deficiency downregulated the transcription of NEDD4L, subsequently enhancing the stability of IKKβ protein. The accumulation of IKKβ caused by the loss of PRDM16 led to the phosphorylation of serine residues on insulin receptor substrate-1 (IRS-1), thereby promoting IRS-1 degradation. Exogenous NEDD4L mitigated podocyte injury induced by PRDM16 knockdown in vitro and attenuated ADR nephropathy in vivo. Our study clarified the role and mechanism of PRDM16 in insulin receptor signaling and podocyte injury, providing a potential therapeutic target for podocytopathies.

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Fig. 1: Renal PRDM16 was decreased in humans and mice with podocytopathies.
Fig. 2: Podocyte-specific Prdm16 deletion aggravated podocyte injury in DN mice.
Fig. 3: PRDM16 protected against podocyte injury and apoptosis in vitro.
Fig. 4: Exogenous PRDM16 attenuated glomerular injury in DN mice.
Fig. 5: PRDM16 alleviated podocyte injury and glomerulosclerosis in ADR nephropathy mice.
Fig. 6: Loss of PRDM16 reduced glucose uptake of podocytes via inhibiting insulin receptor signaling.
Fig. 7: PRDM16 deficiency increased the expression of IKKβ by downregulating the transcription of NEDD4L.
Fig. 8: Podocyte-specific Prdm16 knockout inhibited the insulin receptor pathway and glucose uptake in DN mice.
Fig. 9: NEDD4L rescued podocyte injury caused by PRDM16 deficiency in vitro.
Fig. 10: NEDD4L gene delivery by lentivirus attenuated glomerular injury in ADR nephropathy mice.
Fig. 11: Schematic diagram of mechanism in this study.

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Materials availability

The materials used in this study should be directed to and will be fulfilled by the Lead Contac, Doctor Chun Zhang: drzhangchun@hust.edu.cn. The accession number for the RNA sequencing data reported in this paper is GEO: GSE252685. The link is as follows: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE252685, password: mjcdmioohforvof.

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Acknowledgements

This work was supported by National Key Research and Development Program of China (2024YFC3044900), National Natural Science Foundation of China (82370728, 81974097, 82170773, 82100729, 82100794, 82200808, 82200841, 81800610, 82300843, 82300851, and 82300786), Key Research and Development Program of Hubei Province (2023BCB034), and National Key Research and Development Program of China (2021YFC2500200). We thank the Medical Subcenter of the HUST analytical & testing center in data acquisition. We thank the Cancer Center Laboratory, Wuhan Union Hospital, for sharing the laboratory and equipment.

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  1. These authors contributed equally: Qian Yuan, Ben Tang.

Authors and Affiliations

  1. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Qian Yuan, Ben Tang, Yaru Xie, Yajuan Xie, Yuting Zhu, Hua Su & Chun Zhang

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

    Youhua Liu

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Contributions

QY and CZ designed the study; QY, BT, and HS collected and analyzed the clinical data; QY, BT, YRX, YJX, and YTZ performed animal models; QY, BT, and YRX performed in vitro experiments; QY and BT prepared figures and tables; QY and BT wrote the paper; CZ and HYL revised and approved the final version of the manuscript.

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Correspondence to Chun Zhang.

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The research investigations involving human tissue samples received approval from the Research Ethics Committee of Huazhong University of Science and Technology. All animal experimental procedures were ethically reviewed and approved by the Institutional Animal Care and Use Committee at Tongji Medical College, Huazhong University of Science and Technology.

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Yuan, Q., Tang, B., Xie, Y. et al. PRDM16 deficiency promotes podocyte injury by impairing insulin receptor signaling. Cell Death Differ 32, 1536–1554 (2025). https://doi.org/10.1038/s41418-025-01477-9

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