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

Xiaoyi Zheng, Lauren Higdon, Alexandre Gaudet, Manav Shah, Angela Balistieri, Catherine Li, Patricia Nadai, Latha Palaniappan, Xiaoping Yang, Briana Santo, Brandon Ginley, Xiaoxin X. Wang, Komuraiah Myakala, Pratima Nallagatla, Moshe Levi, Pinaki Sarder, Avi Rosenberg, Jonathan S. Maltzman, Nathalie De Freitas Caires, Vivek Bhalla

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)2059-2076
Number of pages18
Issue number12
StatePublished - Dec 1 2022


  • Esm-1
  • albuminuria
  • basic science
  • chronic kidney disease
  • diabetic nephropathy
  • endocan
  • glomerular disease
  • immunology
  • interferon
  • leukocyte infiltration
  • macrophages
  • podocyte
  • transcriptional profiling
  • transgenic mouse

ASJC Scopus subject areas

  • Nephrology
  • Medicine (miscellaneous)
  • General Medicine


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