Decreased Glomerular Expression of Agrin in Diabetic Nephropathy and Podocytes, Cultured in High Glucose Medium

Yard, Benito A.; Kahlert, Stefan; Engelleiter, R.; Resch, S.; Waldherr, Rüdiger; Groffen, A.J.A.; Heuvel, L.P.W.J. van den; Born, J. van der; Berden, Jo H. M.; Kröger, Stephan; Hafner, M; Woude, Fokko J. van der

doi:10.1159/000052614

Cited by 40 publications

(26 citation statements)

References 31 publications

(60 reference statements)

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“…The concentration of agrin, the major protein core of heparan sulphate proteoglycan, was found to be decreased in the GBM in renal biopsies from patients with diabetic nephropathy. The same phenomenon was observed in vitro, in podocytes cultured in the presence of high glucose, indicating downregulation of the expression of heparan sulphate proteoglycan [24]. It is rather likely that the reported HSPG changes in diabetes are not limited to the kidneys, since reduced HSPG expression was also observed in basement membranes in the skin, in patients with type 1 diabetes suffering from diabetic nephropathy [25].…”

Section: Glomerular Basement Membrane (Gbm)supporting

confidence: 63%

Microvascular basement membranes in diabetes mellitus

Tsilibary

2003

The Journal of Pathology

241

156

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The alterations in the microvascular system of diabetes mellitus patients are responsible for the most devastating complications of this widespread disease. In the kidney, the microangiopathy leads to thickening of the glomerular capillary basement membrane but also to the expansion of the mesangial matrix and thickening of the tubular basement membrane. Several mechanisms are implicated in the pathogenesis of diabetic renal microangiopathy. These include increased synthesis of type IV collagen following hyperglycaemia-induced alteration of the pattern of podocyte-integrin expression, decreased expression of matrix metalloproteinases (MMP-2 and 3), and increased expression of tissue inhibitor of metalloproteinase (TIMP). An altered morphology of podocytes accompanies these basement membrane alterations. Other factors which may contribute to renal matrix accumulation include vascular endothelial growth factor (VEGF), since treatment with anti-VEGF antibodies attenuates glomerular basement membrane thickening, platelet-derived growth factor (PDGF) (B chain) and its receptor, which appear to be highly expressed in mesangial and visceral epithelial cells and might play a role in the development of diabetic nephropathy. Also oxygen radicals/oxidative stress may play a role in matrix accumulation in diabetic nephropathy as aminoguanidine, an inhibitor of the formation of advanced glycation endproducts but with antioxidant properties, attenuates diabetic nephropathy. Retinal diabetic microangiopathy follows much the same principles, be it that microvascular proliferation is a distinctive element in the retina. Nephropathy and retinopathy occur frequently but not always together, indicating that in their multifactorial pathogenesis much remains to be clarified.

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Section: Glomerular Basement Membrane (Gbm)supporting

confidence: 63%

Microvascular basement membranes in diabetes mellitus

Tsilibary

2003

The Journal of Pathology

241

156

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“…This was assessed by immunostaining using antibodies JM-403 and NAH46 that recognize specific HS structures in the GBM. The former has been used to demonstrate the loss of GBM-HS in human and experimental kidney disease, including human membranous nephritis, lupus nephritis, minimal change disease, and diabetic nephropathy 14,39,50 and rat adriamycin nephropathy and Heymann nephritis. 51,52 Although these studies support the theory that reductions in GBM-HS contribute directly to loss of barrier function, labeling with mAb JM-403 was recently reported to be normal in diabetic humans and rats with microalbuminuria, and it was concluded that loss of GBM-HS may be a secondary event that occurs in advanced disease.…”

Section: Discussionmentioning

confidence: 99%

“…39 Here, normal fetal mouse kidney was stained with a panel of three different antisera raised against the C terminus of agrin. Each gave the same pattern, labeling the BM and vascular cleft of S-shaped nephrons and pre-capillary loopstage glomeruli (Figure 2A).…”

Section: Agrn Knockout Mice Synthesize N-terminal Truncated Forms Of mentioning

confidence: 99%

Disruption of Glomerular Basement Membrane Charge through Podocyte-Specific Mutation of Agrin Does Not Alter Glomerular Permselectivity

Harvey

Jarad

Cunningham

et al. 2007

The American Journal of Pathology

156

127

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Glomerular charge selectivity has been attributed to anionic heparan sulfate proteoglycans (HSPGs) in the glomerular basement membrane (GBM). Agrin is the predominant GBM-HSPG, but evidence that it contributes to the charge barrier is lacking, because newborn agrin-deficient mice die from neuromuscular defects. To study agrin in adult kidney, a new conditional allele was used to generate podocyte-specific knockouts. Mutants were viable and displayed no renal histopathology up to 9 months of age. Perlecan, a HSPG normally confined to the mesangium in mature glomeruli, did not appear in the mutant GBM, which lacked heparan sulfate. Moreover, GBM agrin was found to be derived primarily from podocytes. Polyethyleneimine labeling of fetal kidneys revealed anionic sites along both laminae rarae of the GBM that became most prominent along the subepithelial aspect at maturity; labeling was greatly reduced along the subepithelial aspect in agrin-deficient and conditional knockout mice. Despite this severe charge disruption, the glomerular filtration barrier was not compromised, even when challenged with bovine serum albumin overload. We conclude that agrin is not required for establishment or maintenance of GBM architecture. Although agrin contributes significantly to the anionic charge to the GBM, both it and its charge are not needed for glomerular permselectivity. This calls into question whether charge selectivity is a

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“…Synthesis of proteoglycans occurs in all three glomerular cell types, but podocytes are an especially important source of these negatively charged molecules. Proteoglycan synthesis in podocytes is differentially influenced by high ambient glucose and ANG II (83,84); high glucose suppresses the production of agrin's core protein, whereas ANG II decreases synthesis of the core protein and diminishes the sulfation of its side chains (83,84). Podocytes exposed to ANG II decrease the amount of HSPG on their cell surfaces and in the extracellular matrix (83); these results may partly explain the antiproteinuric effect of ACE inhibitors and angiotensin receptor blockers in diabetic nephropathy.…”

Section: Role Of Heparan Sulfate Proteoglycansmentioning

confidence: 99%