The reduction of heparan sulphate in the glomerular basement membrane does not augment urinary albumin excretion

Aoki, Satoshi; Saito-Hakoda, Akiko; Yoshikawa, Takeo; Shimizu, Kyoko; Kisu, Kazuaki; Suzuki, Susumu; Takagi, Kiyoshi; Mizumoto, Shuji; Yamada, Shuhei; Kuppevelt, Toin H. Van; Yokoyama, Atsushi; Matsusaka, Taiji; Sato, Hiroshi; Ito, Sadayoshi; Sugawara, Akira

doi:10.1093/ndt/gfx218

Cited by 15 publications

(14 citation statements)

References 37 publications

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“…Their water and diet were available randomly. The mice were weaned at 4 weeks of age and were thereafter fed with high protein/ high calorie diet for 10 weeks in order to apply a load to the kidney [15]. WT (n = 7) and iNOS-TG (n = 4) mice were sacrificed at their 14 weeks of age.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

Expression and pathophysiological significance of carbohydrate response element binding protein (ChREBP) in the renal tubules of diabetic kidney

et al. 2020

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Carbohydrate response element binding protein (ChREBP), a glucose responsive transcription factor, mainly regulates expression of genes involved in glucose metabolism and lipogenesis. Recently, ChREBP is speculated to be involved in the onset and progression of diabetic nephropathy (DN). However, there exists no report regarding the localization and function of ChREBP in the kidney. Therefore, we analyzed the localization of Chrebp mRNA expression in the wild type (WT) mice kidney using laser microdissection method, and observed its dominant expression in the proximal tubules. In diabetic mice, mRNA expression of Chrebp target genes in the proximal tubules, including Chrebpβ and thioredoxininteracting protein (Txnip), significantly increased comparing with that of WT mice. Co-overexpression of ChREBP and its partner Mlx, in the absence of glucose, also increased TXNIP mRNA expression as well as high glucose in human proximal tubular epithelial cell line HK-2. Since TXNIP is well known to be involved in the production of reactive oxygen species (ROS), we next examined the effect of ChREBP/Mlx co-overexpression, in the absence of glucose, on ROS production in HK-2 cells. Interestingly, ChREBP/Mlx co-overexpression also induced ROS production significantly as well as high glucose. Moreover, both high glucose-induced increase of TXNIP mRNA expression and ROS production were abrogated by ChREBP small interfering RNA transfection. Taken together, high glucose-activated ChREBP in the renal proximal tubules induce the expression of TXNIP mRNA, resulting in the production of ROS which may cause renal tubular damage. It is therefore speculated that ChREBP is involved in the onset and progression of DN.

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Section: Animals and Experimental Designmentioning

confidence: 99%

Expression and pathophysiological significance of carbohydrate response element binding protein (ChREBP) in the renal tubules of diabetic kidney

et al. 2020

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“…Here it is primarily found as part of the proteoglycan, agrin [59,60]. Whether GBM HS plays a role in protein restriction is under debate [59,[61][62][63], although a general note for these and all Glx studies is that there is a need to discriminate between GAG of eGlx and elsewhere (i.e GBM, podocytes and mesangial cells).…”

Section: Glomerular Eglxmentioning

confidence: 99%

Endothelial glycocalyx restoration by growth factors in diabetic nephropathy

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et al. 2019

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The endothelial glycocalyx (eGlx) constitutes the first barrier to protein in all blood vessels. This is particularly noteworthy in the renal glomerulus, an ultrafiltration barrier. Leakage of protein, such as albumin, across glomerular capillaries results in albumin in the urine (albuminuria). This is a hall mark of kidney disease and can reflect loss of blood vessel integrity in microvascular beds elsewhere. We discuss evidence demonstrating that targeted damage to the glomerular eGlx results in increased glomerular albumin permeability. EGlx is lost in diabetes and experimental models demonstrate loss from glomerular endothelial cells. Vascular endothelial growth factor (VEGF)A is upregulated in early diabetes, which is associated with albuminuria. Treatment with paracrine growth factors such as VEGFC, VEGF165b and angiopoietin-1 can modify VEGFA signalling, rescue albumin permeability and restore glomerular eGlx in models of diabetes. Manipulation of VEGF receptor 2 signalling, or a common eGlx biosynthesis pathway by these growth factors, may protect and restore the eGlx layer. This would help to direct future therapeutics in diabetic nephropathy.

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“…By the other hand, it is known that HSPGs are abundant in the glomerular basal membrane and it has been thought to play a major role in the charge-selective glomerular filtration barrier. However, knockout of Ext3 (an enzyme that adds GlcNAc to the fixed tetrasaccharides on the core protein in proteoglycans) in podocytes and glomerular basal membrane did not lead to overt proteinuria ( Aoki et al, 2018 ). Aoki et al (2018) found a bumpy glomerular basal membrane and podocyte effacement by electron microscopy using a Extl3KO mice model compared with Diabetes Mellitus and high sodium intake mice groups, however they had some limitations in their study because the follow-up period was too short for remarkable renal impairments and establishment of hypertension.…”

Section: The Glomerular Endothelial Glycocalyx Is a Barrier That Is Smentioning

confidence: 99%

“…However, knockout of Ext3 (an enzyme that adds GlcNAc to the fixed tetrasaccharides on the core protein in proteoglycans) in podocytes and glomerular basal membrane did not lead to overt proteinuria ( Aoki et al, 2018 ). Aoki et al (2018) found a bumpy glomerular basal membrane and podocyte effacement by electron microscopy using a Extl3KO mice model compared with Diabetes Mellitus and high sodium intake mice groups, however they had some limitations in their study because the follow-up period was too short for remarkable renal impairments and establishment of hypertension. Additionally, renal function tests and HS urine measurements were not assessed in all groups of mice, which would help to support the possible role of HSPGs in the physiology of the GFB.…”

Section: The Glomerular Endothelial Glycocalyx Is a Barrier That Is Smentioning

confidence: 99%

Novel Insights Into the Role of Glycans in the Pathophysiology of Glomerular Endotheliosis in Preeclampsia

2018

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The polysaccharide heparan sulfate is ubiquitously expressed as a proteoglycan in extracellular matrices and on cell surfaces. In the glomerular filtration barrier, the action of the heparan sulfate is directly related to the function of glomerular filtration, mostly attributed to the sulfated domains that occur along the polysaccharide chain, as evidenced by fact that release of fragments of heparan sulfate by heparanase significantly increases the permeability of albumin passage through the glomerular endothelium, event that originates proteinuria. This review aims to show the importance of the structural domains of heparan sulfate in the process of selective permeability and to demonstrate how these domains may be altered during the glomerular inflammation processes that occur in preeclampsia.

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The reduction of heparan sulphate in the glomerular basement membrane does not augment urinary albumin excretion

Abstract: The reduction of HSPG in the GBM did not augment urinary albumin excretion. HSPG's anionic charge appears to contribute little to the glomerular charge barrier.

Cited by 15 publications

References 37 publications

Expression and pathophysiological significance of carbohydrate response element binding protein (ChREBP) in the renal tubules of diabetic kidney

Expression and pathophysiological significance of carbohydrate response element binding protein (ChREBP) in the renal tubules of diabetic kidney

Endothelial glycocalyx restoration by growth factors in diabetic nephropathy

Novel Insights Into the Role of Glycans in the Pathophysiology of Glomerular Endotheliosis in Preeclampsia

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