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 Citations (Scopus)

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

Fingerprint

Non-Receptor Type 1 Protein Tyrosine Phosphatase
Podocytes
Hyperglycemia
Kidney
Wounds and Injuries
Autophagy
High Fat Diet
Streptozocin
Insulin

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury. / Ito, Yoshihiro; Hsu, Ming Fo; Bettaieb, Ahmed; Koike, Shinichiro; Mello, Aline; Calvo-Rubio, Miguel; Villalba, Jose M.; Haj, Fawaz.

In: Metabolism: Clinical and Experimental, Vol. 76, 01.11.2017, p. 56-69.

Research output: Contribution to journalArticle

Ito, Yoshihiro ; Hsu, Ming Fo ; Bettaieb, Ahmed ; Koike, Shinichiro ; Mello, Aline ; Calvo-Rubio, Miguel ; Villalba, Jose M. ; Haj, Fawaz. / Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury. In: Metabolism: Clinical and Experimental. 2017 ; Vol. 76. pp. 56-69.
@article{9c9cb0726b1b4bcd95c8e3159e709dd6,
title = "Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury",
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",
author = "Yoshihiro Ito and Hsu, {Ming Fo} and Ahmed Bettaieb and Shinichiro Koike and Aline Mello and Miguel Calvo-Rubio and Villalba, {Jose M.} and Fawaz Haj",
year = "2017",
month = "11",
day = "1",
doi = "10.1016/j.metabol.2017.07.009",
language = "English (US)",
volume = "76",
pages = "56--69",
journal = "Metabolism: Clinical and Experimental",
issn = "0026-0495",
publisher = "W.B. Saunders Ltd",

}

TY - JOUR

T1 - Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury

AU - Ito, Yoshihiro

AU - Hsu, Ming Fo

AU - Bettaieb, Ahmed

AU - Koike, Shinichiro

AU - Mello, Aline

AU - Calvo-Rubio, Miguel

AU - Villalba, Jose M.

AU - Haj, Fawaz

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - Diabetic nephropathy

KW - Hyperglycemia

KW - Podocytes

KW - Protein tyrosine phosphatase 1B

KW - Renal injury

UR - http://www.scopus.com/inward/record.url?scp=85029175114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029175114&partnerID=8YFLogxK

U2 - 10.1016/j.metabol.2017.07.009

DO - 10.1016/j.metabol.2017.07.009

M3 - Article

C2 - 28987240

AN - SCOPUS:85029175114

VL - 76

SP - 56

EP - 69

JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

SN - 0026-0495

ER -