title: Protective role of growth hormone against hyperhomocysteinemia-induced glomerular injury.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Commonwealth University, 410 N, 12th Street, Richmond, VA 23298, USA.
authors.forename: Caixia
authors.initials: C
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Justine M
authors.initials: JM
authors.lastname: Abais
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Liu
authors.forename: Ningjun
authors.initials: N
authors.lastname: Li
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D013006:Growth Hormone / Q000008:administration & dosage* / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D050199:Podocytes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D013481:Superoxides; D013006:Growth Hormone