Protective role of growth hormone against hyperhomocysteinemia-induced glomerular injury

Caixia Li, Min Xia, Justine M. Abais, Xiaocheng Liu, Ningjun Li, Krishna M. Boini, Pin Lan Li

Research output: Contribution to journalArticle

Abstract

The present study investigated the protective role of growth hormone (GH) against hyperhomocysteinemia (hHcys)-induced activations of reactive oxygen species/hypoxia-inducible factor (HIF)-1α, epithelial-mesenchymal transition (EMT), and consequent glomerular injury. A hHcys model was induced by folate free diet in mice. The urine protein excretion significantly increased while plasma GH levels dramatically decreased in hHcys. Real-time reverse transcription polymerase chain reaction showed that GH receptor (GHR) level increased in the cortex of hHcys mice, which mainly occurred in podocytes as shown by confocal microscopy. Recombinant mouse growth hormone (rmGH) treatment (0.02 mg/kg, once a day for 6 weeks) significantly restored the plasma GH, inhibited GHR upregulation and attenuated proteinuria. Correspondingly, rmGH treatment also blocked hHcys-induced decrease in the expression of podocin, a podocyte slit diaphragm molecule, and inhibited the increases in the expression of desmin, a podocyte injury marker. It was also demonstrated that in hHcys the expression of epithelial markers, p-cadherin and ZO-1, decreased, while the expression of mesenchymal markers, antifibroblast-specific protein 1 (FSP-1) and α-SMA, increased in podocytes, which together suggest the activation of EMT in podocytes. Nicotinamide adenine dinucleotide phosphate oxidase (Nox)-dependent superoxide anion (O2 .-) and hypoxia-inducible factor-1α (HIF-1α) level in the hHcys mice cortex was markedly enhanced. These hHcys-induced EMT enhancement and Nox-dependent O2 .-/HIF-1α activation were significantly attenuated by rmGH treatment. HIF-1α level increased in Hcys-treated cultured podocytes, which were blocked by rmGH treatment. Meanwhile, homocysteine (Hcys)-induced EMT in cultured podocytes was significantly reversed by HIF-1α siRNA. All these results support the view that GH ameliorates hHcys-induced glomerular injury by reducing Nox-dependent O2 .-/HIF-1α signal pathway and EMT.

Original languageEnglish (US)
Pages (from-to)551-561
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume386
Issue number6
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

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Hyperhomocysteinemia
Podocytes
Growth Hormone
Hypoxia-Inducible Factor 1
Epithelial-Mesenchymal Transition
Wounds and Injuries
Somatotropin Receptors
Desmin
Homocysteine
Cadherins
Diaphragm
NADP
Proteinuria
Folic Acid
Confocal Microscopy
Superoxides
Small Interfering RNA
Reverse Transcription
Reactive Oxygen Species
Signal Transduction

Keywords

  • EMT
  • End-stage renal disease
  • Growth hormone
  • Homocysteine

ASJC Scopus subject areas

  • Pharmacology

Cite this

Protective role of growth hormone against hyperhomocysteinemia-induced glomerular injury. / Li, Caixia; Xia, Min; Abais, Justine M.; Liu, Xiaocheng; Li, Ningjun; Boini, Krishna M.; Li, Pin Lan.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 386, No. 6, 01.06.2013, p. 551-561.

Research output: Contribution to journalArticle

Li, Caixia ; Xia, Min ; Abais, Justine M. ; Liu, Xiaocheng ; Li, Ningjun ; Boini, Krishna M. ; Li, Pin Lan. / Protective role of growth hormone against hyperhomocysteinemia-induced glomerular injury. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 2013 ; Vol. 386, No. 6. pp. 551-561.
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