Molecular biology of diabetic glomerulosclerosis

Prete, Dorella Del; Anglani, Franca; Ceol, Monica; D’Angelo, Angela; Forino, M.; Vianello, Daniela; Baggio, Bruno; Gambaro, Giovanni

doi:10.1093/ndt/13.suppl_8.20

Cited by 32 publications

(24 citation statements)

References 42 publications

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“…Expansion of the mesangial area and much protein deposition are observed in glomeruli from patients with chronic glomerulonephritis (25), glomeruloscrelosis (26) or diabetic nephropathy (27). Long lasting deposition of such protein including excessive extracellular matrix in glomeruli is considered to cause the persistent inflammation, cell death, and expansion of mesangial area that lead to dysfunction of the kidney (28 -32).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Prostaglandin E2 in Clearance of Aggregated Protein via Protein Kinase A in Glomeruli

Nagamatsu

Nagao

Koseki

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Recently we immunohistochemically demonstrated that prostaglandin E2 (PGE2) promoted the clearance of aggregated bovine serum albumin (a-BSA) deposited in glomeruli. Herein, we investigated the role of PGE2 and its signal transduction in the disposal of macromolecules in glomeruli. EP2 and EP4 receptor mRNA was detected in glomeruli by RT-PCR analysis. A-BSA was injected twice into mice. Glomeruli were then isolated and incubated. A-BSA gradually disappeared from isolated glomeruli. PGE 2 increased the intracellular cyclic AMP and decreased a-BSA level in glomeruli. Additionally, 8-bromocyclic AMP evoked a loss of a-BSA in isolated glomeruli. The effect of 8-bromo-cyclic AMP on the clearance of a-BSA was abolished by KT 5720 in glomeruli. PGE2 and 8-bromo-cyclic AMP also prompted disposal of a-BSA in cultured mesangial cells. These findings indicate that PGE2 positively regulates the removal of macromolecules via cyclic AMP and protein kinase A in glomeruli, and they provide insight into how to prevent the development of glomerulonephritis and glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

Involvement of Prostaglandin E2 in Clearance of Aggregated Protein via Protein Kinase A in Glomeruli

Nagamatsu

Nagao

Koseki

et al. 2001

Japanese Journal of Pharmacology

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“…Del Prete et al (1998) proposed a pathogenetic scheme whereby VEGF could be a mediator of glomerulosclerosis. Glomerular permeabilization by VEGF might induce both albuminuria and an increased mesangial traffic of growth factors from the circulating blood.…”

Section: Discussionmentioning

confidence: 99%

Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells

Kim¹,

Jung²,

R³

et al. 2000

Journal of Endocrinology

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Diabetic nephropathy associated with hyperglycemia is characterized by glomerular hyperfiltration and endothelial dysfunction. Vascular endothelial growth factor (VEGF) is known to be primarily involved in neoangiogenesis and increased endothelial permeability. The purpose of this study was to investigate VEGF expression in response to high glucose in rat cultured mesangial cells and to identify its signal pathway via protein kinase C (PKC). Rat mesangial cells were cultured with different concentrations of glucose: normal (5 mM -glucose), medium (15 mM -glucose) and high (30 mm -glucose). Calphostin-C as a PKC inhibitor and phorbol myristate acetate (PMA) as a PKC downregulator were instillated into culture media to evaluate the role of PKC in mediating the glucoseinduced increase in VEGF expression. High glucose increased expression of VEGF at the mRNA and protein levels, identified by semi-quantitative RT-PCR and western blotting, within 3 h and in a time-and glucose concentration-dependent manner. Calphostin-C and PMA inhibited glucose-induced increases in VEGF expression at the mRNA and protein levels. In conclusion, high glucose can directly increase VEGF expression in rat mesangial cells via a PKC-dependent mechanism. These results suggest that VEGF could be a potential mediator of glomerular hyperfiltration and proteinuria in diabetic nephropathy.

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“…Such a disruption of signaling may be central to the genesis of endotheliosis, GBM, and mesangial cell alterations and may ultimately lead to glomerulosclerosis. Podocytes may respond to these secondary defects by upregulating the stimulatory VEGF165 isoform, which in turn may enhance glomerular permeability, leading to albuminuria and accumulation of mesangial matrix, as has been postulated for diabetic nephropathy (39).…”

Section: Altered Vegf Expression In Dds Glomerulimentioning

confidence: 91%

Impaired Glomerular Maturation and Lack of VEGF165b in Denys-Drash Syndrome

Schumacher¹,

Jeruschke²,

Eitner³

et al. 2007

Journal of the American Society of Nephrology

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Individuals with Denys-Drash syndrome (DDS) develop diffuse mesangial sclerosis, ultimately leading to renal failure. The disease is caused by mutations that affect the zinc finger structure of the Wilms' tumor protein (WT1), but the mechanisms whereby these mutations result in glomerulosclerosis remain largely obscure. How WT1 regulates genes is likely to be complex, because it has multiple splice forms, binds both DNA and RNA, and associates with spliceosomes. Herein is described that in DDS podocytes, the ratio of both WT1 ؉KTS isoforms C to D differs considerably from that of normal child and adult control podocytes and more closely resembles fetal profiles. Aside from the delay in podocyte maturation, DDS glomeruli show swollen endothelial cells, reminiscent of endotheliosis, together with incompletely fused capillary basement membranes; a dramatic decrease in collagen ␣4(IV) and laminin ␤2 chains; and the presence of immature or activated mesangial cells that express ␣-smooth muscle actin. Because appropriate vascular endothelial growth factor A (VEGF-A) expression is known to be essential for the development and maintenance of glomerular architecture and function, this article addresses the question of whether VEGF-A expression is deregulated in DDS. The data presented here show that DDS podocytes express high levels of the proangiogenic isoform VEGF165, but completely lack the inhibitory isoform VEGF165b. The VEGF165/VEGF165b ratio in DDS resembles that of fetal S-shaped bodies, rather than that of normal child or adult control subjects. The alteration in VEGF-A expression presented here may provide a mechanistic insight into the pathogenesis of DDS.

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Molecular biology of diabetic glomerulosclerosis

Cited by 32 publications

References 42 publications

Involvement of Prostaglandin E2 in Clearance of Aggregated Protein via Protein Kinase A in Glomeruli

Involvement of Prostaglandin E2 in Clearance of Aggregated Protein via Protein Kinase A in Glomeruli

Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells

Impaired Glomerular Maturation and Lack of VEGF165b in Denys-Drash Syndrome

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