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A Murine Model of Irreversible and Reversible Unilateral Ureteric Obstruction
Published on: December 20, 2014
Molecular basis of renal adaptation in a murine model of congenital obstructive nephropathy
Brian Becknell1, Ashley R Carpenter, Jordan L Allen
1Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America ; Division of Pediatric Nephrology, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
Abstract:
Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb (-/-)) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb (-/-) kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb (-/-) kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngal(high) versus Ngal(low) kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb (-/-) mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction.
Insights
Congenital obstructive nephropathy in mice shows kidney adaptation involving urothelial changes. This research identifies new biomarkers for acute kidney injury and potential therapeutic targets.
Area of Science:
- Nephrology
- Developmental Biology
- Molecular Biology
Background:
- Congenital obstructive nephropathy is a significant cause of pediatric chronic kidney disease and a primary reason for kidney transplantation.
- The cellular and molecular mechanisms underlying kidney responses to congenital obstruction remain incompletely understood.
Purpose of the Study:
- To investigate the global transcriptional changes in kidneys affected by congenital obstruction using the megabladder (mgb (-/-)) mouse model.
- To elucidate the pathophysiology of congenital obstructive nephropathy and identify adaptive responses.
Main Methods:
- Global gene expression profiling was performed on kidneys with varying degrees of hydronephrosis in mgb (-/-) mice.
- Analysis focused on identifying activated cellular and molecular pathways, including those related to renal injury and urothelial function.
Main Results:
- Three key pathways—retinoid signaling, steroid hormone metabolism, and renal response to injury—were consistently activated in mgb (-/-) kidneys.
- Increased urothelial proliferation and expression of genes crucial for renal urothelium integrity were observed.
- Neutrophil gelatinase-associated lipocalin (Ngal)/Lipocalin-2 (Lcn2), a marker of acute kidney injury, was elevated in kidneys with higher obstruction grades.
Conclusions:
- The megabladder mouse model demonstrates renal adaptation to progressive hydronephrosis, characterized by significant alterations in renal urothelial morphology and function.
- Novel candidate biomarkers for renal injury were identified, offering potential for improved diagnostics.
- These findings pave the way for developing new therapeutic strategies for progressive renal injury associated with congenital obstruction.
