G1 kinases and transforming growth factor-beta signaling are associated with a growth pattern switch in diabetes-induced renal growth

Kidney Int. 2000 Jul;58(1):162-72. doi: 10.1046/j.1523-1755.2000.00151.x.

Abstract

Background: Diabetes mellitus-induced nephromegaly is thought to involve both hyperplastic and hypertrophic proximal tubule cell growth. The temporal relationship between these growth patterns and the mechanisms that mediate them are unknown.

Methods: Renal growth was assayed in isolated renal proximal tubules harvested from diabetic rats. Diabetes mellitus was induced by streptozotocin.

Results: Following the induction of a diabetic state, there was a progressive increase in the kidney:body weight ratio. This was associated with an increase in 5-bromo-2-deoxyuridine incorporation (marker for hyperplastic cell growth) at day 2, which returned to baselines levels by day 4, and an increase in the protein:DNA ratio (marker for hypertrophic cell growth), which was clearly evident by day 10. Thus, diabetes-induced proximal tubule growth involved an initial hyperplastic, followed by a hypertrophic, growth period. During the hyperplastic growth period, both cdk4/cyclin D (cyclin D) and cdk2/cyclin E (cyclin E) kinase activities were increased. The switch between the growth periods was associated with continued activation of cyclin D, but inhibition of cyclin E kinase. The reduction in cyclin E kinase activity correlated with a reduction in cdk2/cyclin E complex abundance and an increased abundance of cyclin kinase inhibitors in cdk2/cyclin E complexes that did form. Also associated with the switch in growth patterns was a change in transforming growth factor-beta (TGF-beta) receptor expression. During the hyperplastic growth period, TGF-beta receptor II expression was decreased, while during the hypertrophic growth period, there was both a return of receptor II expression to baseline levels and increased expression of receptor I. Consistent with an increase in TGF-beta signaling during hypertrophy, there was an increase in Smad 2/3 protein expression and an increase in the abundance of Smad 2/4 complexes.

Conclusions: Diabetes-induced proximal tubule growth involves an initial hyperplastic growth period that switches to a hypertrophic growth period within a couple of days. The pattern of G1 kinase activity associated with the growth pattern switch demonstrates that the hypertrophy is mediated by a cell cycle-dependent mechanism. Regulation of TGF-beta receptor expression and signaling activity through the Smad protein cascade possibly plays a role in the growth pattern switch.

Publication types

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

MeSH terms

  • Animals
  • CDC2-CDC28 Kinases*
  • Cyclin E
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / metabolism*
  • DNA-Binding Proteins / analysis
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology*
  • G1 Phase / physiology
  • Hyperplasia
  • Hypertrophy
  • Kidney Tubules, Proximal / chemistry
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / pathology*
  • Male
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Transforming Growth Factor beta / analysis
  • Signal Transduction / physiology*
  • Smad2 Protein
  • Smad4 Protein
  • Trans-Activators / analysis
  • Transforming Growth Factor beta / metabolism*

Substances

  • Cyclin E
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad2 protein, rat
  • Smad4 Protein
  • Smad4 protein, rat
  • Trans-Activators
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cdk2 protein, rat
  • Cdk4 protein, rat
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases