Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia

Zhang, Bing; Xiao, Wenyuan; Qiu, Hong; Zhang, Fuming; Moniz, Heather; Jaworski, Alexander; Condac, Eduard; Gutiérrez-Sánchez, Gerardo; Heiß, Christian; Clugston, Robin D.; Azadi, Parastoo; Greer, John J.; Bergmann, Carl; Moremen, Kelley W.; Li, Dean; Linhardt, Robert J.; Esko, Jeffrey D.; Wang, Lianchun

doi:10.1172/jci71090

Cited by 59 publications

(55 citation statements)

References 45 publications

(93 reference statements)

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“…SLIT3 is a secreted protein involved in cytoskeletal regulation, cell migration, and muscle patterning that uses heparan and/or chondroitin sulfatemodified PGs as cofactors and, depending on cellular context, can inhibit Wnt and SDF1/Cxcl12 signaling [35,40,41]. Transgenic deletion of Slit3 and heparan sulfate deficiency both produce congenital diaphragmatic hernia in mice [42,43], a phenotype associated with cryptorchidism in up to 30% of cases [21]. The existence of variably penetrant renal and ureteral anomalies in Slit À/À mice [43] suggests that the intermediate mesoderm is an important SLIT3 developmental target.…”

Section: Developmental Defects In Orl Cryptorchidismmentioning

confidence: 99%

Cryptorchidism in the Orl Rat Is Associated with Muscle Patterning Defects in the Fetal Gubernaculum and Altered Hormonal Signaling1

Barthold

Robbins

Wang

et al. 2014

Biology of Reproduction

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Cryptorchidism, or undescended testis, is a common male genital anomaly of unclear etiology. Hormonal stimulation of the developing fetal gubernaculum by testicular androgens and insulin-like 3 (INSL3) is required for testicular descent. In studies of the orl fetal rat, one of several reported strains with inherited cryptorchidism, we studied hormone levels, gene expression in intact and hormone-stimulated gubernaculum, and imaging of the developing cremaster muscle facilitated by a tissue clearing protocol to further characterize development of the orl gubernaculum. Abnormal localization of the inverted gubernaculum was visible soon after birth. In the orl fetus, testicular testosterone, gubernacular androgen-responsive transcript levels, and muscle-specific gene expression were reduced. However, the in vitro transcriptional response of the orl gubernaculum to androgen was largely comparable to wild type (wt). In contrast, increases in serum INSL3, gubernacular INSL3-responsive transcript levels, expression of the INSL3 receptor, Rxfp2, and the response of the orl gubernaculum to INSL3 in vitro all suggest enhanced activation of INSL3/RXFP2 signaling in the orl rat. However, DNA sequence analysis did not identify functional variants in orl Insl3. Finally, combined analysis of the present and previous studies of the orl transcriptome confirmed altered expression of muscle and cellular motility genes, and whole mount imaging revealed aberrant muscle pattern formation in the orl fetal gubernaculum. The nature and prevalence of developmental muscle defects in the orl gubernaculum are consistent with the cryptorchid phenotype in this strain. These data suggest impaired androgen and enhanced INSL3 signaling in the orl fetus accompanied by defective cremaster muscle development.

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Section: Developmental Defects In Orl Cryptorchidismmentioning

confidence: 99%

Cryptorchidism in the Orl Rat Is Associated with Muscle Patterning Defects in the Fetal Gubernaculum and Altered Hormonal Signaling1

Barthold

Robbins

Wang

et al. 2014

Biology of Reproduction

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“…In our previous studies, we have observed that endothelial Ndst1 deletion leads to reduced N-sulfation and 2-O and 6-O sulfation modifications of endothelial HS [15, 25, 26]. To verify the under sulfated status of the endothelial HS in the Ndst1 f/f Tie2Cre + animals, an FGF-2 binding assay was performed.…”

Section: Resultsmentioning

confidence: 99%

“…The Ndst1 f/f Tie2Cre + mice were generated by breeding Ndst1 f/f mice with transgenic Tie2Cre mice as previously described [15, 26]. All experimental mice were fully backcrossed to C57BL/6 background and handled according to guidelines of the University of Georgia Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

“…Conventional knockout of Ndst1 in mice results in early post-natal death with abnormal lung and forebrain development defects [23, 24]. In previous studies, we generated a conditional Ndst1 ( Ndst1 f/f ) mouse and crossbred with a transgenic mouse expressing Cre recombinase under the Tie2 tyrosine-kinase promoter ( Tie2Cre ) to generate the Ndst1 f/f Tie2Cre + mice in which Ndst1 is specifically ablated in endothelial cells [15, 25, 26]. In the current study, we induced diabetes in the Ndst1 f/f Tie2Cre + mice and their littermate wildtype control Ndst1 f/f Tie2Cre − mice to directly assess the role of endothelial HS in development of renal inflammation and fibrosis in the streptozotocin (STZ)-induced diabetic nephropathy mouse model.…”

Section: Introductionmentioning

confidence: 99%

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Endothelial heparan sulfate deficiency reduces inflammation and fibrosis in murine diabetic nephropathy

Talsma

Katta

Ettema

et al. 2018

Laboratory Investigation

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Inflammation plays a vital role in the development of diabetic nephropathy, but the underlying regulatory mechanisms are only partially understood. Our previous studies demonstrated that, during acute inflammation, endothelial heparan sulfate (HS) contributes to the adhesion and transendothelial migration of leukocytes into perivascular tissues by direct interaction with l-selectin and the presentation of bound chemokines. In the current study, we aimed to assess the role of endothelial HS on chronic renal inflammation and fibrosis in a diabetic nephropathy mouse model. To reduce sulfation of HS specifically in the endothelium, we generated Ndst1f/fTie2Cre+ mice in which N-deacetylase/N-sulfotransferase-1 (Ndst1), the gene that initiates HS sulfation modifications in HS biosynthesis, was expressly ablated in endothelium. To induce diabetes, age-matched male Ndst1f/fTie2Cre− (wild type) and Ndst1f/fTie2Cre+ mice on a C57Bl/6J background were injected intraperitoneally with streptozotocin (STZ) (50 mg/kg) on five consecutive days (N = 10–11/group). Urine and plasma were collected. Four weeks after diabetes induction the animals were sacrificed and kidneys were analyzed by immunohistochemistry and qRT-PCR. Compared to healthy controls, diabetic Ndst1f/fTie2Cre− mice showed increased glomerular macrophage infiltration, mannose binding lectin complement deposition and glomerulosclerosis, whereas these pathological reactions were prevented significantly in the diabetic Ndst1f/fTie2Cre+ animals (all three p < 0.01). In addition, the expression of the podocyte damage marker desmin was significantly higher in the Ndst1f/fTie2Cre− group compared to the Ndst1f/fTie2Cre+ animals (p < 0.001), although both groups had comparable numbers of podocytes. In the cortical tubulo-interstitium, similar analyses show decreased interstitial macrophage accumulation in the diabetic Ndst1f/fTie2Cre+ animals compared to the diabetic Ndst1f/fTie2Cre− mice (p < 0.05). Diabetic Ndst1f/fTie2Cre+ animals also showed reduced interstitial fibrosis as evidenced by reduced density of αSMA-positive myofibroblasts (p < 0.01), diminished collagen III deposition (p < 0.001) and reduced mRNA expression of collagen I (p < 0.001) and fibronectin (p < 0.001). Our studies indicate a pivotal role of endothelial HS in the development of renal inflammation and fibrosis in diabetic nephropathy in mice. These results suggest that HS is a possible target for therapy in diabetic nephropathy.

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“…How this binding affects the complex spatial biology of the ECM is poorly understood, especially given the diverse array of differentially expressed HSPGs, and the variable composition of their HS chains [20]. One mechanism by which HSPGs modulate signaling pathways is by stabilizing gradients of signaling molecules, which provide spatial information to cells during development [24]. In angiogenesis, HSPGs establish a gradient of VEGF, which provides spatial context for the migrating endothelial cells which will form the blood vessel (Fig.…”

Section: Activities Of Hp/hsmentioning

confidence: 99%

Bioengineered heparins and heparan sulfates

Suflita

Linhardt

2016

Advanced Drug Delivery Reviews

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Heparin and heparan sulfates are closely related linear anionic polysaccharides, called glycosaminoglycans, which exhibit a number of important biological and pharmacological activities. These polysaccharides, having complex structures and polydispersity, are biosynthesized in the Golgi of animal cells. While heparan sulfate is a widely distributed membrane and extracellular glycosaminoglycan, heparin is found primarily intracellularly in the granules of mast cells. While heparin has historically received most of the scientific attention for its anticoagulant activity, interest has steadily grown in the multi-faceted role heparan sulfate plays in normal and pathophysiology. The chemical synthesis of these glycosaminoglycans is largely precluded by their structural complexity. Today, we depend on livestock animal tissues for the isolation and the annual commercial production of hundred ton quantities of heparin used in the manufacture of anticoagulant drugs and medical device coatings. The variability of animal-sourced heparin and heparan sulfates, their inherent impurities, the limited availability of source tissues, the poor control of these source materials and their manufacturing processes, suggest a need for new approaches for their production. Over the past decade there have been major efforts in the biotechnological production of these glycosaminoglycans, driven by both therapeutic applications and as probes to study their natural functions. This review focuses on the complex biology of these glycosaminoglycans in human health and disease, and the use of recombinant technology in the chemoenzymatic synthesis and metabolic engineering of heparin and heparan sulfates.

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Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia

Cited by 59 publications

References 45 publications

Cryptorchidism in the Orl Rat Is Associated with Muscle Patterning Defects in the Fetal Gubernaculum and Altered Hormonal Signaling1

Cryptorchidism in the Orl Rat Is Associated with Muscle Patterning Defects in the Fetal Gubernaculum and Altered Hormonal Signaling1

Endothelial heparan sulfate deficiency reduces inflammation and fibrosis in murine diabetic nephropathy

Bioengineered heparins and heparan sulfates

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