Uremic Toxin Mixture for Endothelial Cell Vasculopathy Modeling
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Solution Overview
Problem
Current methods lack an effective way to model and treat uremic vasculopathy, a major cause of cardiovascular complications and increased mortality in patients with chronic kidney disease, due to unclear roles of uremic toxins in endothelial cell dysfunction.
Innovation Solution
A medium composition using a uremic toxin mixture including urea, uric acid, and optionally indoxyl sulfate or advanced glycation end products is used to create an endothelial cell model of uremic vasculopathy, allowing for the simulation of endothelial cell dysfunction similar to that in chronic kidney disease patients, enabling drug screening and toxicity testing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If a single uremic substance is used to model endothelial cell dysfunction, then the model is simple and easy to establish, but it cannot accurately reflect the complex pathogenesis of uremic vasculopathy caused by multiple uremic toxins
Solution Approach 1:
The patent combines multiple uremic toxins (urea, uric acid, indoxyl sulfate, creatinine, and advanced glycation end products) into a single uremic toxin mixture for use in the cell culture medium. This merging approach allows the model to reflect the complex pathogenesis of uremic vasculopathy caused by multiple uremic toxins acting synergistically, while maintaining ease of model establishment through a unified mixture formulation.
Solution Approach 2:
The invention uses a composite uremic toxin mixture comprising multiple different uremic substances at specific concentrations. This composite approach accurately reflects the complex pathogenesis of uremic vasculopathy, where multiple uremic toxins act together to cause endothelial cell dysfunction, rather than using a single substance that would oversimplify the disease mechanism.
2Reliability
If patient serum is used directly to create a uremic model, then the model reflects actual patient conditions, but it lacks standardization and cannot be easily reproduced across different studies
Solution Approach 1:
The patent defines specific concentration parameters for each uremic toxin in the mixture (urea: 25-50 mM, uric acid: 0.5-1.0 mM, indoxyl sulfate: 0.1-0.5 mM, creatinine: 0.1-0.5 mM, advanced glycation end products: 10-50 μg/mL). These standardized parameter changes allow the model to accurately reflect patient conditions while ensuring reproducibility across different studies and laboratories.
Solution Approach 2:
Instead of using actual patient serum directly, the invention creates a standardized copy or simulation of the uremic toxin profile found in patient serum. This copying approach maintains the accuracy of reflecting actual patient conditions while enabling standardization and easy reproduction across different research settings.
3Productivity
If conventional cell lines are used for drug screening, then the screening process is simple and fast, but it cannot effectively evaluate drugs for uremic vasculopathy due to lack of disease-specific characteristics
Solution Approach 1:
The patent applies preliminary action by first treating endothelial cells with the standardized uremic toxin mixture to induce uremic vasculopathy characteristics before performing drug screening. This preliminary induction of disease-specific characteristics ensures that subsequent drug evaluations are performed on cells that accurately represent the uremic vasculopathy state, improving both the accuracy and efficiency of drug screening for this specific condition.
Data Source
AI summary
The present invention relates to a model of uremic vasculopathy and uses of the same. More specifically, the present invention relates to: a medium composition for producing an endothelial cell model of uremic vasculopathy, using a uremic toxin mixture that includes urea and uric acid and may further include indoxyl sulfate, creatinine, or advanced glycation end products (AGEs); a preparation method for an endothelial cell model of uremic vasculopathy, including the step of treating endothelial cells with the uremic toxin mixtures; an endothelial cell model of uremic vasculopathy, prepared by the preparation method; screening and toxicity testing methods, using the model, for agents that inhibit or treat uremic vasculopathy. The uremic toxin mixtures including urea and uric acid of the present invention, merely by using the uremic toxins among other various kinds of uremic toxins, may enable simulating a uremic milieu in endothelial cells conveniently in a manner similar to when using the uremic serum of an actual patient with chronic kidney disease. In addition, the uremic toxin mixture of the present invention, when used for preparing an endothelial cell model of uremic angiopathy, may produce an endothelial cell model capable of reflecting various signs of uremic vasculopathy. Furthermore, by using endothelial cells differentiated from induced pluripotent stem cells when preparing the endothelial cell model of uremic vasculopathy model, it is possible to produce an endothelial cell model of uremic vasculopathy with genetic characteristics reflected therein, which may be beneficially used in customized drug screening for the treatment of patients with uremic vasculopathy, the development of new drugs, toxicity testing, and the like.