Effect of insulin on ACE2 activity and kidney function in the non-obese diabetic mouse

PLoS One. 2014 Jan 6;9(1):e84683. doi: 10.1371/journal.pone.0084683. eCollection 2014.

Abstract

We studied the non-obese diabetic (NOD) mice model because it develops autoimmune diabetes that resembles human type 1 diabetes. In diabetic mice, urinary albumin excretion (UAE) was ten-fold increased at an "early stage" of diabetes, and twenty-fold increased at a "later stage" (21 and 40 days, respectively after diabetes diagnosis) as compared to non-obese resistant controls. In NOD Diabetic mice, glomerular enlargement, increased glomerular filtration rate (GFR) and increased blood pressure were observed in the early stage. In the late stage, NOD Diabetic mice developed mesangial expansion and reduced podocyte number. Circulating and urine ACE2 activity were markedly increased both, early and late in Diabetic mice. Insulin administration prevented albuminuria, markedly reduced GFR, blood pressure, and glomerular enlargement in the early stage; and prevented mesangial expansion and the reduced podocyte number in the late stage of diabetes. The increase in serum and urine ACE2 activity was normalized by insulin administration at the early and late stages of diabetes in Diabetic mice. We conclude that the Diabetic mice develops features of early kidney disease, including albuminuria and a marked increase in GFR. ACE2 activity is increased starting at an early stage in both serum and urine. Moreover, these alterations can be completely prevented by the chronic administration of insulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Blood Glucose
  • Blood Pressure
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / enzymology*
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / physiopathology*
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Female
  • Insulin / administration & dosage
  • Insulin / pharmacology
  • Kidney / enzymology*
  • Kidney / pathology
  • Kidney / physiopathology*
  • Kidney Function Tests
  • Male
  • Mice
  • Mice, Inbred NOD
  • Peptidyl-Dipeptidase A / blood
  • Peptidyl-Dipeptidase A / metabolism*
  • Peptidyl-Dipeptidase A / urine

Substances

  • Blood Glucose
  • Insulin
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2

Grant support

This work was supported by grants from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (ISCIII-FEDER. PI081688), and Fundación Senefro. J.P. is funded in part through the project ISCIII-FEDER PI10/01370. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.