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

Yoshihiro Ito, Ming Fo Hsu, Ahmed Bettaieb, Shinichiro Koike, Aline Mello, Miguel Calvo-Rubio, Jose M. Villalba, Fawaz Haj

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)56-69
Number of pages14
JournalMetabolism: Clinical and Experimental
Volume76
DOIs
StatePublished - Nov 1 2017

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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