Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice
| Autor: | Xiaoyi Zheng, C. Li, Moshe Levi, M. Shah, N. Caires, Santo Ba, A. Balistieri, L. Higdon, P. Nadai, Xiaoxin X. Wang, L. Palaniappan, Pinaki Sarder, Brandon Ginley, Ximing J. Yang, J. Maltzman, P. Nallagatla, Komuraiah Myakala, A. Gaudet, Vivek Bhalla, Avi Z. Rosenberg |
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| Rok vydání: | 2022 |
| Předmět: |
Kidney
medicine.medical_specialty Endothelial Cell-Specific Molecule 1 business.industry Inflammation General Medicine medicine.disease Podocyte medicine.anatomical_structure Endocrinology Internal medicine Diabetes mellitus medicine Albuminuria CXCL11 medicine.symptom business Infiltration (medical) Original Investigation |
| Zdroj: | Kidney360 |
| ISSN: | 2641-7650 |
| DOI: | 10.34067/kid.0001712022 |
| Popis: | BACKGROUND: 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. METHODS: Using 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. RESULTS: In 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, including Ackr2 and Cxcl11. CONCLUSIONS: We 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. |
| Databáze: | OpenAIRE |
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