Proteomic analysis identifies insulin-like growth factor-binding protein-related protein-1 as a podocyte product

Matsumoto, Takayuki; Hess, Sonja; Kajiyama, Hiroshi; Sakairi, Toru; Saleem, Moin A.; Mathieson, Peter W.; Nojima, Yoshihisa; Kopp, Jeffrey B.

doi:10.1152/ajprenal.00597.2009

Cited by 20 publications

(15 citation statements)

References 37 publications

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“…Soluble factors including cytokines, retinoids, and steroid hormones have been reported to upregulate nephrin gene expression (17,28,32). We recently identified secreted proteins using conditioned medium derived from human podocyte culture by a proteomics approach (18). Further study will be required to identify autocrin and/or paracrine activators for nephrin gene expression.…”

Section: Discussionmentioning

confidence: 99%

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Sakairi

Abe

Jat

et al. 2010

American Journal of Physiology-Renal Physiology

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We transformed mouse podocytes by ectopic expression of cyclin-dependent kinase 4 (CDK4). Compared with podocytes transformed with a thermo-sensitive SV40 large T antigen mutant tsA58U19 (tsT podocytes), podocytes transformed with CDK4 (CDK4 podocytes) exhibited significantly higher expression of nephrin mRNA. Synaptopodin mRNA expression was significantly lower in CDK4 podocytes and in tsT podocytes under growth-permissive conditions (33°C) compared with tsT podocytes under growth-restricted conditions (37°C), which suggests a role for cell cycle arrest in synaptopodin mRNA expression. Confluent CDK4 podocytes showed significantly higher mRNA expression levels for nephrin, synaptopodin, Wilms tumor 1, podocalyxin, and P-cadherin compared with subconfluent cultures. We carried out experiments to clarify roles of various factors in the confluent podocyte cultures; our findings indicate that cell-cell contact promotes expression of five podocyte marker genes studied, that cellular quiescence increases synaptopodin and podocalyxin mRNA expression, and that soluble factors play a role in nephrin mRNA expression. Our findings suggest that CDK4 podocytes are useful tools to study podocyte biology. Furthermore, the role of cell-cell contact in podocyte gene expression may have relevance for podocyte function in vivo.cyclin-dependent kinase 4; SV40 large T antigen; nephrin; synaptopodin; Wilms tumor-1; P-cadherin PODOCYTE CULTURES, ESPECIALLY podocyte cell lines transformed by thermosensitive SV40 large T antigen (SV40 T), have been widely used to study podocyte biology (19,25). However, as we recently reported in studies on a generation of mouse and human podocyte cell lines, podocytes transformed by thermosensitive SV40 T (tsT) exhibit phenotypic differences compared with podocytes in vivo, with reduced expression of certain differentiation marker genes (13, 24).Cyclin-dependent kinase 4 (CDK4), a catalytic subunit of the cyclin D-CDK4 serine/threonine kinase complex, is a critical regulator of the cell cycle. CDK4 is the first kinase activated by mitogenic signals. The kinase activity of CDK4 is specifically involved in progression through G1, via phosphorylation of retinoblastoma (Rb) family members (4). Recently, Ramirez et al. (22) immortalized human bronchial epithelial cells by ectopic expression of CDK4 and human telomerase (hTERT). Microarray analysis showed that CDK4/hTERTimmortalized cells showed significantly different gene expression profiles compared with cells immortalized with human papiloma viral oncoproteins E6/E7 or SV40T and that CDK4-transformed cells clustered with primary bronchial epithelial cells. In addition, recent studies showed that cells immortalized with CDK4 are useful tools to study physiology and pathophysiology (8,23,30).We set out to develop an alternative approach to transforming podocytes by comparing the phenotype among primary cells, CDK4-transformed podocytes (CDK4-podocytes) and thermosensitive SV40 T mutant tsA58U19 (tsT-podocytes). We found that CDK4-podocytes and tsT-podocyt...

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Section: Discussionmentioning

confidence: 99%

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Sakairi

Abe

Jat

et al. 2010

American Journal of Physiology-Renal Physiology

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“…[72][73][74][75][76][77] Podocyte differentiation was induced by thermo-shifting the cells from 33°C to 37°C for 10 days. Podocytes were then treated for Proximal Tubule Cell Culture…”

Section: Podocyte Culturementioning

confidence: 99%

G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes

Wang

Edelstein

Gafter

et al. 2015

JASN

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159

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Obesity and diabetes mellitus are the leading causes of renal disease. In this study, we determined the regulation and role of the G protein-coupled bile acid receptor TGR5, previously shown to be regulated by high glucose and/or fatty acids, in obesity-related glomerulopathy (ORG) and diabetic nephropathy (DN). Treatment of diabetic db/db mice with the selective TGR5 agonist INT-777 decreased proteinuria, podocyte injury, mesangial expansion, fibrosis, and CD68 macrophage infiltration in the kidney. INT-777 also induced renal expression of master regulators of mitochondrial biogenesis, inhibitors of oxidative stress, and inducers of fatty acid b-oxidation, including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), and Nrf-1. Increased activity of SIRT3 was evidenced by normalization of the increased acetylation of mitochondrial superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2) observed in untreated db/db mice. Accordingly, INT-777 decreased mitochondrial H 2 O 2 generation and increased the activity of SOD2, which associated with decreased urinary levels of H 2 O 2 and thiobarbituric acid reactive substances. Furthermore, INT-777 decreased renal lipid accumulation. INT-777 also prevented kidney disease in mice with dietinduced obesity. In human podocytes cultured with high glucose, INT-777 induced mitochondrial biogenesis, decreased oxidative stress, and increased fatty acid b-oxidation. Compared with normal kidney biopsy specimens, kidney specimens from patients with established ORG or DN expressed significantly less TGR5 mRNA, and levels inversely correlated with disease progression. Our results indicate that TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation, establishing a role for TGR5 in inhibiting kidney disease in obesity and diabetes.

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“…Expression has also been reported in proximal tubule cells, but primarily only in response to insults, mitogens, or second messengers (14,20,41,45,62,63). There is a dearth of information regarding IGFBP7 in the kidney, and what is available is contradictory, showing expression in the glomerulus and alternatively in distal and proximal tubule cells (17,35,42,65,72).…”

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confidence: 99%

Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells

Emlet

Pastor-Soler

Marciszyn

et al. 2017

American Journal of Physiology-Renal Physiology

112

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We have characterized the expression and secretion of the acute kidney injury (AKI) biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in human kidney epithelial cells in primary cell culture and tissue. We established cell culture model systems of primary kidney cells of proximal and distal tubule origin and observed that both proteins are indeed expressed and secreted in both tubule cell types in vitro. However, TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin, while IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin. In human kidney tissue, strong staining of IGFBP7 was seen in the luminal brush-border region of a subset of proximal tubule cells, and TIMP-2 stained intracellularly in distal tubules. Additionally, while some tubular colocalization of both biomarkers was identified with the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, both biomarkers could also be seen alone, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion demonstrated enhancement of secretion of both markers early after reperfusion. This work provides a rationale for further investigation of these markers for their potential role in the pathogenesis of acute kidney injury.

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Proteomic analysis identifies insulin-like growth factor-binding protein-related protein-1 as a podocyte product

Cited by 20 publications

References 37 publications

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes

Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells

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