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Growth factor expression in the obstructed developing and mature rat kidney
H T Nguyen1, A A Thomson, B A Kogan
1Department of Urology and Anatomy, University of California School of Medicine, San Francisco, USA.
Abstract:
The purpose of this study is to evaluate the role of keratinocyte growth factor (KGF), transforming growth factor-alpha (TGF-alpha), and their receptors in altered renal growth caused by complete ureteral obstruction in the developing kidney. Neonatal and adult rats underwent complete unilateral ureteral ligation or sham operation. The kidneys were harvested at 1, 5, 10, 20, and 30 days after obstruction. Renal growth and development was assessed by histology and immunohistocytochemical localization of vimentin, cytokeratin and smooth muscle-alpha actin. Cellular proliferation was measured by [3H]thymidine labeling index of all cells. RNase protection assays were used to quantify mRNA encoding for KGF, KGF receptor, TGF-alpha, and epidermal growth factor (EGF) receptor. Ureteral obstruction in the developing kidneys resulted in decreased DNA synthesis, rapid parenchymal loss, myofibroblast proliferation in the interstitium, decreased tubular epithelial cells formation, and development of cystic dysplasia. In comparison, obstruction in the mature kidneys resulted in transient growth in the medullary ductal cells, parenchymal loss, and myofibroblast proliferation at a later time, lymphocytic infiltration in the interstitium but not cystic dysplasia. KGF and KGF receptor mRNA levels were increased in obstructed neonatal kidneys. Similarly, TGF-alpha and EGF receptor mRNA levels were increased. Delayed and more moderate increases in KGF, KGF receptor, and TGF-alpha expression were also seen in the obstructed mature kidneys. Of importance, the amount of EGF receptor mRNA was not increased in the obstructed compared with the contralateral or sham-operated adult kidneys. This study suggests that obstruction alters the normal expression pattern of KGF, TGF-alpha, and their receptors in renal development. These changes may be responsible for the impaired renal growth and altered development seen in ureteral obstruction of the kidneys. Although some changes are similar to those seen in the adult kidney, the increased expression of TGF-alpha and cystic dysplasia are unique to neonatal obstruction.
Insights
Complete ureteral obstruction in developing kidneys impairs growth by altering keratinocyte growth factor (KGF) and transforming growth factor-alpha (TGF-alpha) signaling, leading to cystic dysplasia.
Area of Science:
- Nephrology
- Developmental Biology
- Molecular Biology
Background:
- Ureteral obstruction significantly impacts kidney development and function.
- Growth factors and their receptors play critical roles in renal development and response to injury.
Purpose of the Study:
- To investigate the role of keratinocyte growth factor (KGF), transforming growth factor-alpha (TGF-alpha), and their receptors in renal growth alterations caused by ureteral obstruction in developing kidneys.
- To compare the effects of obstruction in neonatal versus adult kidneys.
Main Methods:
- Neonatal and adult rats underwent unilateral ureteral ligation or sham operation.
- Kidneys were harvested at various time points for histological, immunohistochemical, and molecular analyses.
- Measurements included DNA synthesis, cellular proliferation ([3H]thymidine labeling), and mRNA levels of KGF, KGF receptor, TGF-alpha, and EGF receptor via RNase protection assays.
Main Results:
- Neonatal obstruction led to decreased DNA synthesis, parenchymal loss, myofibroblast proliferation, reduced tubular formation, and cystic dysplasia.
- Adult obstruction caused transient medullary ductal cell growth, parenchymal loss, myofibroblast proliferation, and lymphocytic infiltration, but not cystic dysplasia.
- Obstructed neonatal kidneys showed increased mRNA for KGF, KGF receptor, and TGF-alpha; adult kidneys showed delayed, moderate increases in these factors, with no significant change in EGF receptor mRNA.
Conclusions:
- Ureteral obstruction alters the expression of KGF, TGF-alpha, and their receptors during renal development.
- These molecular changes likely contribute to impaired renal growth and abnormal development observed in neonatal ureteral obstruction.
- Increased TGF-alpha expression and cystic dysplasia are unique features of neonatal obstruction compared to adult obstruction.