Glomerular epithelial cells transform to myofibroblasts: early but not late removal of TGF-β1 reverses transformation

Sam, Ramin; Wanna, Linda; Gudehithlu, Krishnamurthy P.; Garber, Sandra L.; Dunea, George; Arruda, José A.L.; Singh, Ashok K.

doi:10.1016/j.trsl.2006.04.003

Cited by 33 publications

(38 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we observed that hypercholesterolemia þ RAS blunted tubular expression of the epithelial marker E-cadherin, the loss of which constitutes an early indicator of EMT [31]. Similarly, mesenchymal markers and indices of EMT such as a-SMA and vimentin were upregulated in hypercholesterolemia þ RAS, not only in tubular epithelial cells and interstitial myofibroblasts but also in glomerular visceral and parietal epithelial cells, implying active EMT [27][28][29] possibly relevant to both periglomerular and interstitial fibrosis. The abundance of a-SMA positive cells is particularly indicative of irreversible transformation of epithelial cells into myofibroblasts, cells that are now capable of producing extracellular matrix and promoting fibrosis [8].…”

Section: Discussionmentioning

confidence: 70%

“…Ã P < 0.05 vs. normal, y P < 0.05 vs. hypercholesterolemia þ RAS. tubular and glomerular epithelial cells acquire mesenchymal/fibroblast characteristics and change into myofibroblasts [27][28][29][30]. Although EMT plays a prominent role in embryogenesis and tissue repair, unopposed it may evolve into organ fibrosis [31] and is probably involved in progressive fibrotic diseases of the heart, lung, liver, and kidney.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Simvastatin abates development of renal fibrosis in experimental renovascular disease

Chade

Zhu

Grande³

et al. 2008

Journal of Hypertension

View full text Add to dashboard Cite

Simvastatin upregulates inhibitors of transforming growth factor-beta signaling, attenuates epithelial-to-mesenchymal transition, and decreases renal fibrosis in hypercholesterolemia + renal artery stenosis. These lipid-lowering-independent effects result in improvement of renal function, suggesting clinically valuable potential for statins in preserving the stenotic kidney and limiting deterioration of renal function in atherosclerotic renovascular disease.

show abstract

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Simvastatin abates development of renal fibrosis in experimental renovascular disease

Chade

Zhu

Grande³

et al. 2008

Journal of Hypertension

View full text Add to dashboard Cite

show abstract

“…71 Tubular cells may change their differentiation during hypoxia, 3,72 and podocytes have also been reported to be capable of undergoing changes of differentiation in vitro. 73,74 We found potential markers for a change of differentiation in the microarray gene expression analysis of glomeruli from NSC, eg, down-regulation of the epithelial marker keratin 1 (q Ͻ 0.01) and up-regulation of the mesenchymal markers S100 calcium binding protein A4 (q Ͻ 0.01) and smooth muscle actin, ␣2 (q Ͻ 0.01) (Supplemental Table S1, see http://ajp.amjpathol.org). These observations could point to a role of hypoxia for potential plasticity in podocyte differentiation.…”

Section: Discussionmentioning

confidence: 99%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1␣ only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. Hypoxia is considered a pivotal factor contributing to tubular atrophy and interstitial fibrosis, which are factors for the progression of renal disease. 1 The evidence in support of this hypothesis derives mostly from experimental animal studies.2-5 Most of these have focused on the tubulointerstitial space with little attention being paid to the glomerulus. The cellular response to hypoxia is largely mediated by heterodimeric transcription factors, the hypoxia-inducible factors (HIFs).2 The cellular levels of the HIF1␣ and HIF2␣ subunits (HIF␣) of HIF (gene symbols HIF1A and HIF2A) are controlled mainly by posttranslational protein modification. Under normoxia HIF␣ is degraded by the von Hippel-Lindau tumor suppressor protein. This process is regulated by oxygen-dependent hydroxylation of HIF␣ through specific prolyl hydroxylases. Under hypoxic conditions degradation of HIF␣ ceases and the stabilized protein can function as a transcription factor.2 In the renal glomerulus, a functional role of HIF1␣ 6 -8 and HIF2␣ 9 has been documented in podocytes of rodents. Recently, glomerular podocyte-specific deletion of von Hippel-Lindau tumor suppressor protein was achieved in mice, resulting in podocyte-specific overactivity of HIF with induction of HIF target genes. 6,8

show abstract

“…The glomerular epithelial cell line was originally obtained from Dr. J. L. Kreisberg (Kreisberg et al 1978) and has been used in many of our previous studies (e.g., Sam et al 2006). Primary rat mesangial cells were cultured from freshly isolated glomeruli as previously described (Singh et al 2004).…”

Section: Culture Of Omental Cells From Activated Rat Omentummentioning

confidence: 99%

Stromal cells cultured from omentum express pluripotent markers, produce high amounts of VEGF, and engraft to injured sites

et al. 2008

Self Cite

View full text Add to dashboard Cite

When rat omentum becomes activated by intraperitoneal injection of inert polydextran particles, these particles are rapidly surrounded by cells that express markers of adult stem cells (SDF-1alpha, CXCR4, WT-1) and of embryonic pluripotent cells (Oct-4, Nanog, SSEA-1). We have cultured such cells, because they may offer a convenient source of adult stem cells, and have found that they retain stem cell markers and produce high levels of vascular endothelial growth factor for up to ten passages. After systemic or local injection of these cultured cells into rats with acute injury of various organs, the cells specifically engraft at the injured sites. Thus, our experiments show that omental stromal cells can be cultured from activated omentum, and that these cells exhibit stem cell properties enabling them to be used for repair and possibly for the regeneration of damaged tissues.

show abstract

Glomerular epithelial cells transform to myofibroblasts: early but not late removal of TGF-β1 reverses transformation

Cited by 33 publications

References 16 publications

Simvastatin abates development of renal fibrosis in experimental renovascular disease

Simvastatin abates development of renal fibrosis in experimental renovascular disease

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Stromal cells cultured from omentum express pluripotent markers, produce high amounts of VEGF, and engraft to injured sites

Contact Info

Product

Resources

About