Angiotensin converting-enzyme inhibitor treatment reduces glomerular p16INK4 and p27Kip1 expression in diabetic BBdp rats

Diabetologia. 1999 Dec;42(12):1425-32. doi: 10.1007/s001250051314.

Abstract

Aims/hypothesis: Renal hypertrophy occurs early in diabetes mellitus and precedes the development of glomerulosclerosis and tubulointerstitial fibrosis. We have previously shown that cultured mesangial cells exposed to high glucose are arrested in the G1-phase of the cell cycle and undergo cellular hypertrophy. High glucose-mediated induction of p27Kip1, an inhibitor of cyclin-dependent kinases, is essential in this process. Further investigations have also shown that p27Kip1 and p21Cip1, other cyclin-dependent kinase inhibitors, are up regulated in the kidneys of mice with Type I (insulin-dependent) as well as Type II (non-insulin-dependent) diabetes mellitus. Our study was undertaken to test a potential effect of short-term treatment with the angiotensin-converting enzyme inhibitor enalapril on the glomerular expression of the cyclin-dependent kinase inhibitors p16INK4, p21Cip1, and p27Kip1 in BBdp rats, an autoimmune model of Type I diabetes.

Methods: We evaluated p16INK4, p21Cip1, and p27Kip1 protein expression in isolated glomeruli by western blots. We also assessed p27Kip1 positive glomerular cells by immunohistochemistry.

Results: Glomerular expression of all three cyclin-dependent kinase inhibitors were stimulated in BBdp rats compared with non-diabetic BBdr animals. Enalapril treatment for 3 weeks, started after the onset of diabetes, reduced the glomerular expression of p16INK4 and p27Kip1 but not of p21Cip1. Enalapril also prevented the increase in kidney weights observed in BBdp rats but had no effect on systolic blood pressure or glucose concentrations.

Conclusion/interpretation: Our data show that enalapril attenuates the glomerular expression of cyclin-dependent kinase inhibitors in diabetes and suggest a molecular mechanism of how angiotensin-converting enzyme inhibitors prevent renal hypertrophy in diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Blotting, Western
  • Cell Cycle Proteins*
  • Cyclin-Dependent Kinase Inhibitor p16 / analysis
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclins / analysis
  • Cyclins / genetics
  • Enalapril / pharmacology*
  • Gene Expression / drug effects*
  • Immunohistochemistry
  • Kidney Glomerulus / chemistry
  • Kidney Glomerulus / metabolism*
  • Male
  • Microtubule-Associated Proteins / analysis
  • Microtubule-Associated Proteins / genetics*
  • Rats
  • Rats, Inbred BB
  • Tumor Suppressor Proteins*

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Cdkn1a protein, rat
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Microtubule-Associated Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Enalapril