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Deficiency of the Src homology phosphatase 2 in podocytes is associated with renoprotective effects in mice under hyperglycemia

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Abstract

Diabetic nephropathy (DN) is a significant complication of diabetes and the leading cause of end-stage renal disease. Hyperglycemia-induced dysfunction of the glomerular podocytes is a major contributor to the deterioration of renal function in DN. Previously, we demonstrated that podocyte-specific disruption of the Src homology phosphatase 2 (Shp2) ameliorated lipopolysaccharide-induced renal injury. This study aims to evaluate the contribution of Shp2 to podocyte function under hyperglycemia and explore the molecular underpinnings. We report elevated Shp2 in the E11 podocyte cell line under high glucose and the kidney under streptozotocin- and high-fat diet-induced hyperglycemia. Consistently, Shp2 disruption in podocytes was associated with partial renoprotective effects under hyperglycemia, as evidenced by the preserved renal function. At the molecular level, Shp2 deficiency was associated with altered renal insulin signaling and diminished hyperglycemia-induced renal endoplasmic reticulum stress, inflammation, and fibrosis. Additionally, Shp2 knockdown in E11 podocytes mimicked the in vivo deficiency of this phosphatase and ameliorated the deleterious impact of high glucose, whereas Shp2 reconstitution reversed these effects. Moreover, Shp2 deficiency attenuated high glucose-induced E11 podocyte migration. Further, we identified the protein tyrosine kinase FYN as a putative mediator of Shp2 signaling in podocytes under high glucose. Collectively, these findings suggest that Shp2 inactivation may afford protection to podocytes under hyperglycemia and highlight this phosphatase as a potential target to ameliorate glomerular dysfunction in DN.

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Acknowledgements

Research in the Haj laboratory was funded by the National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK095359 and R01DK090492, the National Institute of Environmental Health Sciences grant P42ES04699, and NIFA grant CA-D*-NTR-7836H. Dr. Haj is a Co-Leader of the Endocrinology and Metabolism Core of UC Davis Mouse Metabolic Phenotyping Center, which is funded by U24DK092993. Dr. Hsu was supported by National Institute on Alcohol Abuse and Alcoholism grant R21AA027633. Dr. Afkarian was supported by the grant R01DK104706 from the National Institute of Diabetes and Digestive and Kidney Diseases. The Light Microscopy Imaging Facility (UC Davis) is supported by National Institutes of Health grant 1S10RR019266.

Funding

Research in the Haj laboratory was funded by the National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK095359 and R01DK090492, the National Institute of Environmental Health Sciences grant P42ES04699, and NIFA grant CA-D*-NTR-7836H. Dr. Haj is a Co-Leader of the Endocrinology and Metabolism Core of UC Davis Mouse Metabolic Phenotyping Center, which is funded by U24DK092993. Dr. Hsu was supported by National Institute on Alcohol Abuse and Alcoholism grant R21AA027633. Dr. Afkarian was supported by the grant R01DK104706 from the National Institute of Diabetes and Digestive and Kidney Diseases.

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  1. Yoshihiro Ito

    Present address: Department of Endocrinology and Diabetes, and Department of CKD Initiatives/Nephrology, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan

Authors and Affiliations

  1. Department of Nutrition, University of California Davis, Davis, CA, 95616, USA

    Ming-Fo Hsu, Yoshihiro Ito & Fawaz G. Haj

  2. Division of Nephrology, Department of Internal Medicine, University of California Davis, Sacramento, CA, 95817, USA

    Maryam Afkarian

  3. Comprehensive Cancer Center, University of California Davis, Sacramento, CA, 95817, USA

    Fawaz G. Haj

  4. Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA, 95817, USA

    Fawaz G. Haj

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MH, YI, and FH contributed to the study design and interpretation of the data. MH and YI conducted the experiments and analyzed the data. MH wrote the first draft of the manuscript. MH, YI, MA, and FH reviewed and edited the manuscript. All authors read and approved the submission of the manuscript.

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Hsu, MF., Ito, Y., Afkarian, M. et al. Deficiency of the Src homology phosphatase 2 in podocytes is associated with renoprotective effects in mice under hyperglycemia. Cell. Mol. Life Sci. 79, 516 (2022). https://doi.org/10.1007/s00018-022-04517-6

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