The Unilateral Ureteral Obstructionmouse (UUO) model is an essential tool for studying kidney diseases, particularly renal fibrosis. Renal fibrosis is a common feature of chronic kidney disease (CKD) and can eventually lead to severe kidney failure. By using the UUO model, researchers can learn more about the disease’s progression, identify potential therapeutic targets, and test potential treatments.
Basics and Methodology
Introduction to CKD and renal fibrosis
Chronic kidney disease (CKD) is a global health concern that affects millions of people worldwide. It is characterized by the gradual loss of kidney function over time, which can ultimately result in kidney failure and the need for dialysis or transplantation. CKD encompasses a wide range of conditions, from mild kidney damage to end-stage renal disease (ESRD). One of the critical factors driving the progression of CKD is renal fibrosis.
Renal fibrosis is a pathological process in which healthy kidney tissue is replaced by an excess of extracellular matrix components, such as collagen, resulting in the formation of fibrous, non-functional tissue. This fibrotic process impairs the kidney’s ability to filter waste and maintain proper fluid and electrolyte balance, further exacerbating CKD. Renal fibrosis is triggered by various factors, including inflammation, oxidative stress, and the activation of specific molecular pathways.
Methodology for UUO mouse model
The UUO model involves a surgical procedure where researchers create a one-sided obstruction in the ureter, usually with a silk thread, most commonly of the left one.
In the UUO model, stagnant urine flow leads to an increase in hydrostatic pressure, initially causing dilation of the collecting ducts. This pressure is then transmitted to both distal and proximal tubules. The elevated proximal tubule pressure has two consequences: a reduction in glomerular filtration rate (GFR) and mechanical stretching damage to tubular epithelial cells. This obstruction results in inflammation, cell death, and fibrosis. This surgical procedure is an attractive model for researchers because it is relatively simple and reproducible, and the pathology can be evaluated in 7-14 days.
Pathophysiological changes observed in the UUO model
It has been observed that in UUO-affected kidneys, there is significant structural damage, a reduced number of tubules, tubular atrophy, enlarged tubules, cystic expansion, infiltration of inflammatory cells, tubular epithelial cell apoptosis, tubulointerstitial fibrosis, and accumulation of extracellular matrix (ECM).
Renal fibrosis and histology
Tubulointerstitial fibrosis
Tubulointerstitial fibrosis involves the excessive accumulation of ECM components, such as collagen, in the renal interstitium (the space between the renal tubules). The buildup of ECM leads to the formation of fibrous tissue, which disrupts the normal kidney architecture and impairs kidney function.
Histological assessment of renal fibrosis often involves staining techniques, such as Masson’s trichrome, Sirius Red, or periodic acid-Schiff (PAS) staining. These stains help visualize collagen deposition and other fibrotic changes in the kidney tissue.
Tubular atrophy
Tubular atrophy is characterized by the shrinkage or loss of the epithelial cells lining the renal tubules. This process is often accompanied by tubular dilation, where the tubules’ lumens become enlarged.
Inflammation
In renal fibrosis, the kidney tissue becomes infiltrated by various inflammatory cells, such as macrophages, lymphocytes, and neutrophils. These immune cells release cytokines and growth factors that contribute to inflammation, oxidative stress, and ECM production, further exacerbating fibrosis.
Challenges and Limitations of the UUO Model
Understanding the complex interplay between these factors and their roles in renal fibrosis is critical for the development of novel therapeutic strategies to prevent or reverse the progression of CKD. Researchers have been using animal models, such as the UUO mouse model, to investigate the molecular and cellular mechanisms underlying renal fibrosis and identify potential therapeutic targets.
References
Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments. Biomolecules. 2019 Apr; 9(4): 141. Published online 2019 Apr 8. doi: 10.3390/biom9040141
