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

Kidney360. 2022 Jul 19;3(12):2059-2076. doi: 10.34067/KID.0001712022. eCollection 2022 Dec 29.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Albuminuria* / immunology
  • Animals
  • Diabetes Mellitus, Experimental* / complications
  • Diabetes Mellitus, Experimental* / genetics
  • Diabetes Mellitus, Experimental* / metabolism
  • Diabetic Nephropathies* / genetics
  • Diabetic Nephropathies* / immunology
  • Disease Susceptibility / metabolism
  • Endothelial Cells* / metabolism
  • Inflammation* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Transcription Factors / metabolism


  • Transcription Factors
  • endothelial cell-specific molecule-1, mouse