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Metabolism. 2017 Nov;76:56-69. doi: 10.1016/j.metabol.2017.07.009. Epub 2017 Aug 8.

Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury.

Author information

1
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, United States.
2
Department of Cell Biology, Physiology and Immunology, Agrifood Campus of International Excellence ceiA3, University of Cordoba, 14014 Cordoba, Spain.
3
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, United States; Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, United States; Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, United States. Electronic address: fghaj@ucdavis.edu.

Abstract

OBJECTIVE:

Diabetic nephropathy is one of the most devastating complications of diabetes, and growing evidence implicates podocyte dysfunction in disease pathogenesis. The objective of this study was to investigate the contribution of protein tyrosine phosphatase 1B (PTP1B) in podocytes to hyperglycemia-induced renal injury.

METHODS:

To determine the in vivo function of PTP1B in podocytes we generated mice with podocyte-specific PTP1B disruption (hereafter termed pod-PTP1B KO). Kidney functions were determined in control and pod-PTP1B KO mice under normoglycemia and high-fat diet (HFD)- and streptozotocin (STZ)-induced hyperglycemia.

RESULTS:

PTP1B expression increased in murine kidneys following HFD and STZ challenges. Under normoglycemia control and pod-PTP1B KO mice exhibited comparable renal functions. However, podocyte PTP1B disruption attenuated hyperglycemia-induced albuminuria and renal injury and preserved glucose control. Also, podocyte PTP1B disruption was accompanied with improved renal insulin signaling and enhanced autophagy with decreased inflammation and fibrosis. Moreover, the beneficial effects of podocyte PTP1B disruption in vivo were recapitulated in E11 murine podocytes with lentiviral-mediated PTP1B knockdown. Reconstitution of PTP1B in knockdown podocytes reversed the enhanced insulin signaling and autophagy suggesting that they were likely a consequence of PTP1B deficiency. Further, pharmacological attenuation of autophagy in PTP1B knockdown podocytes mitigated the protective effects of PTP1B deficiency.

CONCLUSIONS:

These findings demonstrate that podocyte PTP1B deficiency attenuates hyperglycemia-induced renal damage and suggest that PTP1B may present a therapeutic target in renal injury.

KEYWORDS:

Diabetic nephropathy; Hyperglycemia; Podocytes; Protein tyrosine phosphatase 1B; Renal injury

PMID:
28987240
PMCID:
PMC5690491
DOI:
10.1016/j.metabol.2017.07.009
[Indexed for MEDLINE]
Free PMC Article

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