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

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 mig...

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Bibliographic Details
Published in:Laboratory investigation 2018-04, Vol.98 (4), p.427-438
Main Authors: Talsma, Ditmer T., Katta, Kirankumar, Ettema, Marieke A.B., Kel, Berna, Kusche-Gullberg, Marion, Daha, Moh R., Stegeman, Coen A., van den Born, Jacob, Wang, Lianchun
Format: Article
Language:English
Subjects:
Ablation
Animals
Biosynthesis
Chemokines
Collagen
Collagen (type I)
Collagen (type III)
Deposition
Desmin
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - complications
Diabetic Nephropathies - etiology
Diabetic Nephropathies - pathology
Diabetic nephropathy
Endothelial Cells - enzymology
Endothelium
Fibronectin
Fibrosis
Gene expression
Heparan sulfate
Heparitin Sulfate - metabolism
Immunohistochemistry
Infiltration
Inflammation
Kidney - immunology
Kidney - pathology
Kidneys
L-selectin
Leukocyte migration
Leukocytes
Macrophages
Male
Mannose
Mice
Mice, Inbred C57BL
Mice, Transgenic
N-Deacetylase
N-deacetylase/N-sulfotransferase
N-sulfotransferase
Nephropathy
Regulatory mechanisms (biology)
Streptozocin
Sulfates
Sulfation
Sulfotransferase
Sulfotransferases - metabolism
Urine
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Summary: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.
ISSN:0023-6837
1530-0307
DOI:10.1038/s41374-017-0015-2