Reply: New Insight Into the Cardiovascular Prognostic Importance of Endocan

Çelik, Mustafa; Sökmen, Erdoğan; Sivri, Serkan; Erer, Murat

doi:10.1177/0003319719845961

Cited by 3 publications

(3 citation statements)

References 5 publications

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“…Although others have reported correlations of Esm-1 with kidney diseases [79][80][81][82] , cardiovascular diseases 79,[83][84][85][86] , and cancer [87][88][89][90][91] , data linking Esm-1 to DKD have been mixed. For example, Ekiz-Bilir et al showed a direct correlation between serum Esm-1 and the degree of albuminuria in patients with type 2 diabetes mellitus 92 , while Cikrikcioglu et al reported the opposite 93 .…”

Section: Discussionmentioning

confidence: 99%

“…Although others have reported correlations of Esm-1 with kidney diseases (79)(80)(81)(82), cardiovascular diseases (79,(83)(84)(85)(86), and cancer (87)(88)(89)(90)(91), data linking Esm-1 to DKD have been mixed. For example, Ekiz-Bilir et al Esm-1 knockout Wild-type control Using cross-sectional data, we do not observe a lower circulating level of Esm-1 in patients with diabetes and albuminuria.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice

et al. 2022

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BackgroundDiabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored.MethodsUsing hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli.ResultsIn DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease–promoting and interferon (IFN)-related genes, includingAckr2andCxcl11.ConclusionsWe demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice

et al. 2022

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“…Esm-1 transcription is stimulated by pro-inflammatory cytokines 18 , and progressive DKD is characterized by inflammation 15,[31][32][33][34][35] . Although others have reported correlations of Esm-1 with kidney diseases 23,[36][37][38] , cardiovascular diseases 23,[39][40][41][42] , and cancer [43][44][45][46][47] , data linking Esm-1 to DKD are mixed. For example, Ekiz-Bilir et al showed a direct correlation between serum Esm-1 and the degree of albuminuria in patients with type 2 diabetes mellitus 48 , while Cikrikcioglu et al reported the opposite 49 .…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice

Zheng

Higdon

Gaudet

et al. 2021

Preprint

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Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. In this study, we show that lower circulating Esm-1 predicts progressive stages of albuminuria in patients with diabetes. In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. Using hydrodynamic tail-vein injection, we show that over-expression of either mouse or human Esm-1 reduces diabetes-induced albuminuria relative to saline-injected controls independent of leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice increases the degree of diabetes-induced albuminuria versus wild-type controls. Mechanistically, over-expression of Esm-1 attenuates diabetes-induced podocyte injury. By glomerular RNAseq, we identify that Esm-1 attenuates diabetes-induced up-regulation of interferon-stimulated genes, and Esm-1 inhibits expression of kidney disease-promoting and interferon-related genes, including Ackr2 and Cxcl11. In conclusion, we demonstrate that Esm-1 protects against diabetes-induced albuminuria, and podocytopathy, possibly through select interferon signaling.

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