G1 kinases and transforming growth factor-beta signaling are associated with a growth pattern switch in
1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8856, USA.
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.
Insights
Diabetes causes kidney enlargement through initial cell proliferation (hyperplasia) followed by cell growth (hypertrophy). This switch involves cell cycle regulators and TGF-beta signaling pathways in diabetic nephropathy.
Area of Science:
- Nephrology
- Cell Biology
- Endocrinology
Background:
- Diabetes mellitus can lead to nephromegaly, characterized by proximal tubule cell hyperplasia and hypertrophy.
- The precise timing and underlying mechanisms of these cellular growth patterns in diabetic nephropathy remain unclear.
Purpose of the Study:
- To investigate the temporal sequence of hyperplastic and hypertrophic growth in diabetic nephropathy.
- To elucidate the molecular mechanisms, including cell cycle regulation and growth factor signaling, that mediate these growth patterns.
Main Methods:
- Isolated renal proximal tubules from streptozotocin-induced diabetic rats were analyzed.
- Kidney-to-body weight ratio, cell proliferation markers (5-bromo-2-deoxyuridine incorporation), and cell size markers (protein:DNA ratio) were measured.
- Activities of cyclin-dependent kinases (cdk4/cyclin D, cdk2/cyclin E), expression of TGF-beta receptors, and Smad protein signaling were assessed.
Main Results:
- Diabetic rats exhibited increased kidney weight, with initial hyperplastic growth (day 2) followed by hypertrophic growth (day 10).
- Cell cycle kinase activities shifted, with increased cyclin D and cyclin E during hyperplasia, and sustained cyclin D with inhibited cyclin E during hypertrophy.
- Transforming growth factor-beta (TGF-beta) receptor expression and Smad signaling were altered, suggesting a role in mediating the switch between growth phases.
Conclusions:
- Diabetic nephropathy involves a sequential hyperplastic to hypertrophic proximal tubule cell growth pattern.
- Cell cycle-dependent mechanisms, regulated by G1 kinase activity, mediate the transition to hypertrophy.
- Modulation of TGF-beta receptor expression and Smad signaling pathways likely plays a critical role in regulating this growth pattern switch.
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