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Phenotypic changes and cell cycle activation in early tubulointerstitial injury of rat adriamycin nephrosis
Yujing Shu1, Sachi Hoshi, Shinsuke Tomari
1Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
Abstract:
Tubular response, including phenotypic changes against a variety of injuries, is an initial event that promotes tubulointerstitial injuries. Using the progressive kidney disease model of rat adriamycin (ADR) nephrosis, the present study focused on the cell cycle activation and phenotypic changes that occur in the tubuli in early tubulointerstitial injury in ADR nephrosis. At 12 weeks, experimental animals developed overt nephrosis with tubulointerstitial injury, which correlated well with the degree of proteinuria and incidence of glomerulosclerosis. Initial pathology of the tubuli showed a slight dilatation of tubuli, which tended to occur in individual nephrons. Immunohistochemistry demonstrated that vimentin-positive tubuli and osteopontin (OPN)-positive tubuli were associated mostly with proliferating cell nuclear antigen expression. Protein levels of OPN in the renal cortex were correlated with the level of proteinuria by western blotting. Vimentin- and OPN-expressing tubuli were tightly associated with a peritubular influx of alpha-smooth muscle actin (SMA)-positive cells or ED-1-positive cells. In addition, we found thrombomodulin+/ TUNEL+ (dUTP-biotin nick-end labeling) peritubular endothelial cells and ED-1+/alpha-SMA+ cells at an early stage among interstitial inflammatory cells. These results suggest that cell cycle activation in tubular cells forms the background for the phenotypic tubular changes that are involved in chronic tubulointerstitial injury in ADR nephrosis.
Insights
Tubular cell cycle activation and phenotypic changes are early events in adriamycin (ADR) nephrosis, contributing to progressive kidney disease. These changes correlate with proteinuria and glomerulosclerosis, indicating a role in tubulointerstitial injury.
Area of Science:
- Nephrology
- Cell Biology
- Pathology
Background:
- Tubulointerstitial injuries are promoted by tubular responses and phenotypic changes.
- Adriamycin (ADR) nephrosis in rats serves as a progressive kidney disease model.
Purpose of the Study:
- To investigate cell cycle activation and phenotypic changes in renal tubules during early tubulointerstitial injury in ADR nephrosis.
- To correlate these changes with disease progression markers like proteinuria and glomerulosclerosis.
Main Methods:
- Utilized a rat model of adriamycin (ADR) nephrosis.
- Employed immunohistochemistry to detect vimentin, osteopontin (OPN), proliferating cell nuclear antigen, alpha-smooth muscle actin (SMA), and ED-1.
- Performed western blotting to quantify OPN protein levels.
- Used TUNEL (dUTP-biotin nick-end labeling) to identify apoptotic cells.
Main Results:
- Early tubulointerstitial injury in ADR nephrosis showed tubular dilatation, vimentin and OPN expression associated with cell proliferation.
- Increased OPN protein levels in the renal cortex correlated with proteinuria.
- Vimentin- and OPN-positive tubules were linked to infiltrating alpha-SMA and ED-1 positive cells.
- Thrombomodulin+/TUNEL+ peritubular endothelial cells and ED-1+/alpha-SMA+ interstitial cells were observed early.
Conclusions:
- Cell cycle activation in tubular cells precedes and underlies phenotypic tubular changes in ADR nephrosis.
- These alterations contribute to the development of chronic tubulointerstitial injury.
- The findings highlight early cellular events critical for understanding progressive kidney disease.
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