Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease

Kidney Int. 1997 Jan;51(1):230-43. doi: 10.1038/ki.1997.28.


In Milan normotensive (MNS) rats glomerulosclerosis and interstitial fibrosis develop spontaneously in the absence of hypertension. Renal changes were sequentially assessed in these rats between 2 and 10 months of age. At 10 months, rats were characterized by heavy proteinuria, increased serum creatinine, focal or global glomerulosclerosis in 51 +/- 12% of the glomeruli as well as tubulointerstitial injury involving > 25% of the section area. Cell injury in podocytes (evidenced as increased expression of desmin and by electron microscopy) and interstitial fibroblasts (increased expression of alpha-smooth muscle actin) and mild glomerular hypertrophy were witnessed as early as three to four months of age and preceded glomerulosclerosis and interstitial fibrosis. Only minor evidence of mesangial cell activation (as assessed by glomerular (de novo alpha-smooth muscle actin or type I collagen expression or increased cell proliferation) was noted throughout the observation period. Later stages of the disease were characterized by glomerular and/or tubulointerstitial macrophage influx and osteopontin expression (a chemoattractant), mild accumulation of lymphocytes, platelets, fibrinogen, as well as by a progressive accumulation of various matrix proteins. Progressive renal disease in MNS rats is thus noteworthy for the relative lack of mesangial cell activation. Rather, early podocyte damage, induced by yet unknown mechanisms, may underlie the development of glomerulosclerosis and subsequent interstitial fibrosis.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Age Factors
  • Animals
  • Blood Pressure
  • Cell Division / physiology
  • Cytokines / metabolism
  • Desmin / metabolism
  • Evaluation Studies as Topic
  • Extracellular Space / chemistry
  • Extracellular Space / metabolism
  • Fibrosis
  • Glomerulosclerosis, Focal Segmental / pathology*
  • Glomerulosclerosis, Focal Segmental / physiopathology
  • Hypertrophy
  • Immunoenzyme Techniques
  • Intermediate Filament Proteins / metabolism
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / ultrastructure
  • Kidney Tubules / chemistry
  • Kidney Tubules / metabolism
  • Macrophages / physiology
  • Microscopy, Immunoelectron
  • Monocytes / physiology
  • Muscle, Smooth / chemistry
  • Muscle, Smooth / metabolism
  • Nephritis, Interstitial / pathology*
  • Nephritis, Interstitial / physiopathology
  • Osteopontin
  • Proteinuria / pathology
  • Proteinuria / physiopathology
  • Rats
  • Rats, Inbred Strains
  • Renal Insufficiency / pathology
  • Renal Insufficiency / physiopathology
  • Sialoglycoproteins / metabolism


  • Actins
  • Cytokines
  • Desmin
  • Intermediate Filament Proteins
  • Sialoglycoproteins
  • Spp1 protein, rat
  • Osteopontin