Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease

Rudnicki, Michael A.; Perco, Paul; Enrich, Julia; Eder, Susanne; Heininger, Dorothea; Bernthaler, Andreas; Wiesinger, Martin; Sarközi, Rita; Noppert, Susie-Jane; Schramek, Herbert; Mayer, Bernd; Oberbauer, Rainer; Mayer, Gert

doi:10.1038/labinvest.2008.158

Cited by 97 publications

(80 citation statements)

References 39 publications

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“…The reason for this apparent discrepancy is largely beyond the scope of this study but may be because of differences in HIF downstream regulation by the extent and duration of HIF activation. 20 Downstream effectors investigated in this study were EPO, VEGF, HO-1, and Cu/Zn-SOD, which all were induced by CoCl 2 . EPO is known to exert renoprotective, antiapoptotic effects, protecting peritubular capillaries and preventing glomerulosclerosis, 21,22 and VEGF may ameliorate kidney injury.…”

Section: Discussionmentioning

confidence: 79%

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

173

145

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Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetesinduced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 79%

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

173

145

View full text Add to dashboard Cite

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“…Of interest in this regard, both EGF and TGF-␤ 1 were shown to increase VEGF expression in several tubuloepithelial cell lines, an effect that, at least in the case of TGF-␤ 1 , occurs through ERK1/2 activation. 47,48 Thus, such a mechanism might contribute to the VEGF upregulation by PTHrP(1-36) in MCT cells. In any event, these findings are consistent with an important role of ERK1/2 signaling pathway in the EMT process.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone–Related Protein Promotes Epithelial–Mesenchymal Transition

Ardura

Rayego‐Mateos

Rámila³

et al. 2010

Journal of the American Society of Nephrology

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Epithelial-mesenchymal transition (EMT) is an important process that contributes to renal fibrogenesis. TGF-␤1 and EGF stimulate EMT. Recent studies suggested that parathyroid hormone-related protein (PTHrP) promotes fibrogenesis in the damaged kidney, apparently dependent on its interaction with vascular endothelial growth factor (VEGF), but whether it also interacts with TGF-␤ and EGF to modulate EMT is unknown. Here, PTHrP(1-36) increased TGF-␤1 in cultured tubuloepithelial cells and TGF-␤ blockade inhibited PTHrP-induced EMT-related changes, including upregulation of ␣-smooth muscle actin and integrin-linked kinase, nuclear translocation of Snail, and downregulation of E-cadherin and zonula occludens-1. PTHrP(1-36) also induced EGF receptor (EGFR) activation; inhibition of protein kinase C and metalloproteases abrogated this activation. Inhibition of EGFR activation abolished these EMT-related changes, the activation of ERK1/2, and upregulation of TGF-␤1 and VEGF by PTHrP (1-36). Moreover, inhibition of ERK1/2 blocked EMT induced by either PTHrP(1-36), TGF-␤1, EGF, or VEGF. In vivo, obstruction of mouse kidneys led to changes consistent with EMT and upregulation of TGF-␤1 mRNA, p-EGFR protein, and PTHrP. Taken together, these data suggest that PTHrP, TGF-␤, EGF, and VEGF might cooperate through activation of ERK1/2 to induce EMT in renal tubuloepithelial cells.

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“…VEGF is secreted by macrophages [45], DCs [46], T-cells [47] and renal tubular epithelial cells [48] and is often found after injury or in tumour-related diseases. It is also an important factor for differentiation of haematopoietic progenitor cells [49,50].…”

Section: Generation and Activation Of Murine Mdscsmentioning

confidence: 99%

Myeloid Derived Suppressor Cells and Their Role in Diseases

Kong¹,

Fuchsberger

Xiang

et al. 2013

CMC

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Abstract:Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitors that can play a major role in tumour development and chronic inflammation. The importance of the suppressive function of MDSCs was first suggested by studies involving cancer patients and cancer-bearing mice. In addition, recent studies have demonstrated that MDSCs can also be involved in many other pathological conditions. MDSCs have unique ways of abrogating an immune response in addition to those utilised by other immune-suppressive cell types, for example via the induction of arginase-1 and consequent upregulation in reactive oxygen species (ROS) production. Due to their heterogeneity, they further can express a variety of lineage markers, which overlap with other myeloid cell types such as Gr1, CD11b, MHCII lo , Ly6C and Ly6G, making it difficult to identify them by surface phenotype alone. The disparity between mouse and human MDSCs further complicates the identification of these elusive cell populations. In this review, we will summarise the recent updates on the methods for eliciting and studying different MDSC subsets, including newly proposed surface phenotypes, as well as insights into how their function is being characterised in both mice and humans. In addition, exciting new discoveries suggesting their involvement across a number of different pathological settings, such as sepsis, autoimmunity and Leishmaniasis, will be discussed.

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Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease

Cited by 97 publications

References 39 publications

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Parathyroid Hormone–Related Protein Promotes Epithelial–Mesenchymal Transition

Myeloid Derived Suppressor Cells and Their Role in Diseases

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