Angiopoietin-Like-4, a Potential Target of Tacrolimus, Predicts Earlier Podocyte Injury in Minimal Change Disease

PLoS One. 2015 Sep 9;10(9):e0137049. doi: 10.1371/journal.pone.0137049. eCollection 2015.


Podocyte injury plays central roles in proteinuria and kidney dysfunction, therefore, identifying specific biomarker to evaluate earlier podocyte injury is highly desirable. Podocyte-secreted angiopoietin-like-4 (Angptl4) mediates proteinuria in different types of podocytopathy. In the present study, we established an experimental minimal change disease (MCD) rat model, induced by adriamycin (ADR) and resulted in definite podocyte injury, to identify the dynamic changes in Angptl4 expression. We also investigated the direct effects of tacrolimus on Angptl4 and podocyte repair. We determined that the glomerular Angptl4 expression was rapidly upregulated and reached a peak earlier than desmin, an injured podocyte marker, in the ADR rats. Furthermore, this upregulation occurred prior to heavy proteinuria and was accompanied by increased urinary Angptl4. We observed that the Angptl4 upregulation occurred only when podocyte was mainly damaged since we didn't observe little Angptl4 upregulation in MsPGN patients. In addition, we observed the glomerular Angptl4 mainly located in injured podocytes rather than normal podocytes. Moreover, we found that tacrolimus treatment significantly promoted podocyte repair and reduced glomerular and urinary Angptl4 expression at an earlier stage with a significant serum Angptl4 upregulation. And similar results were confirmed in MCD patients. In conclusion, this study represents the first investigation to demonstrate that Angptl4 can predict podocyte injury at earlier stages in MCD and the identification of earlier podocyte injury biomarkers could facilitate the prompt diagnosis and treatment of patients with podocytopathy, as well as determination of the prognosis and treatment efficacy in these diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-like 4 Protein
  • Angiopoietins / biosynthesis*
  • Angiopoietins / blood
  • Angiopoietins / genetics
  • Animals
  • Disease Models, Animal
  • Doxorubicin / toxicity
  • Humans
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Nephrosis, Lipoid / chemically induced
  • Nephrosis, Lipoid / drug therapy
  • Nephrosis, Lipoid / genetics*
  • Nephrosis, Lipoid / pathology
  • Podocytes / drug effects
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Proteinuria
  • Rats
  • Tacrolimus / administration & dosage*


  • ANGPTL4 protein, rat
  • Angiopoietin-like 4 Protein
  • Angiopoietins
  • Doxorubicin
  • Tacrolimus

Grant support

This study was supported by research grants from the National Basic Research Program of China 973 Program (No. 2012CB517602), the National Natural Science Foundation of China (81370812), research fund for the Doctoral Program of Ministry of Education of China (20122307110018), the Special Grade of China Postdoctoral Science Foundation (No. 201003463), and the Heilongjiang Postdoctoral Science Research Foundation (No. LBHQ10028).