Efficacy Evaluation in a Mouse UUO Model from Renal Function to Fibrosis Histopathology

An Unmet Market Need: 788 million Patients, No Approved Antifibrotic Drug

According to the GBD 2023 study, approximately 788 million adults aged 20 years and older worldwide had chronic kidney disease (CKD) in 2023, including more than 100 million in China. Renal fibrosis is a common pathway through which different forms of CKD progress to end‑stage disease. Current first‑line therapies—renin–angiotensin system (RAS) blockers, SGLT2 inhibitors, finerenone, and GLP‑1 receptor agonists—target upstream disease drivers and hemodynamic changes. To date, no drug has been approved specifically for the treatment of renal fibrosis. This unmet need is one reason why emerging modalities, including oligonucleotide therapeutics, are entering this field.

An overview of the global development pipeline

The tables below summarize representative drug programs directly relevant to renal fibrosis (Information is current as of August 2026. This list is not exhaustive; please refer to ClinicalTrials.gov and company announcements for the latest updates).

Small molecules and biologics

Oligonucleotide therapeutics

Programs with a direct antifibrotic mechanism remain relatively scarce; most drugs act on upstream processes such as inflammation and hemodynamics. Among oligonucleotide programs, farabursen has advanced to Phase III, whereas lademirsen was discontinued after failing to demonstrate an eGFR benefit in Phase II. Preclinical findings do not necessarily translate into clinical benefit, making the predictive value of disease models and evaluation endpoints particularly important.

A case study of efficacy evaluation in the Jennio Biotech UUO model

The unilateral ureteral obstruction (UUO) model develops characteristic renal interstitial fibrosis within 7–14 days. Its reproducibility makes it a commonly used model for early screening of antifibrotic drugs and mechanistic studies.

Study design

Animals: Male C57BL/6 mice, 8 weeks of age.

Model induction: The ureter on one side was exposed through an abdominal or flank surgical approach. Two ligatures were placed along its upper‑to‑middle segment using surgical silk to create complete urinary tract obstruction.

Groups: Sham (exposure of the left ureter without ligation), UUO (ureteral ligation), and UUO + X (ureteral ligation followed by treatment with test drug X).

Endpoints: General observations included alertness, appetite, activity, and mortality. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Histopathological assessments included hematoxylin and eosin (H&E) staining, Sirius Red or Masson’s trichrome staining, and immunohistochemistry (IHC) for collagen I and α‑smooth muscle actin (α‑SMA).

Applications

1. Lead compound screening and dose exploration: The short 7–14‑day study period enables rapid comparison of multiple candidate molecules and doses.
2. Mechanistic studies: Target validation focused on key fibrotic processes, including TGF‑β1/Smad signaling, connective tissue growth factor (CTGF), and extracellular matrix (ECM) deposition.
3. Head‑to‑head comparison with a positive control: Comparison of the antifibrotic effects of test compounds and existing standard treatments within the same model system.
4. Combination therapy evaluation: Exploration of regimens such as a test compound combined with an SGLT2 inhibitor.

In addition, the model’s limitations should also be clearly acknowledged. UUO is a model of rapidly developing fibrosis caused by acute obstruction, which differs from the slow progression of human CKD. It is well suited to mechanistic studies and early screening. For long‑term treatment evaluation in chronic disease, follow‑on studies in models with a slower course, such as adenine‑ or folic acid‑induced models, are recommended (see the comparison below).

Evaluating oligonucleotide therapeutics in this model system

1. Literature basis. As early as 2007, a study published in the American Journal of Nephrology reported that HSP47 siRNA significantly reduced the expression of types I, III, and IV collagen and attenuated interstitial fibrosis in a mouse UUO model. Therapies targeting HSP47 subsequently advanced to Phase II clinical development for hepatic fibrosis. In addition, oligonucleotides can accumulate in proximal renal tubules through reabsorption, making the kidney a relatively favorable organ for delivery beyond the liver. The clinical‑stage program farabursen provides an example.
2. Current status and opportunities. Currently, Systematic in vivo efficacy evaluation of oligonucleotide therapeutics in renal fibrosis models remains largely exploratory, and established evaluation standards are still lacking. This also creates an opportunity: teams that develop reliable models and endpoint frameworks may help establish methodological benchmarks for the field.
3. Endpoint scalability. The existing renal function, histopathology, and IHC assessments can be supplemented with project‑specific endpoints, including target gene mRNA knockdown in kidney tissue by quantitative PCR (qPCR), target protein levels by Western blotting (WB) or IHC, semiquantitative assessment of fibrotic area, and kidney injury molecule‑1 (KIM‑1) or neutrophil gelatinase‑associated lipocalin (NGAL). These endpoints cover key steps from target validation in the kidney to antifibrotic efficacy. Each evaluation plan should be tailored to the target and molecular modality.

Appendix: Comparison of commonly used renal fibrosis models

For a more detailed comparison of the UUO and adenine models, see our previous article, “Adenine‑Induced Nephropathy and UUO Models in Renal Fibrosis Research: Characteristics and Selection for Different Applications.”