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Updated: Jul 1, 2026
A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis
Published on: October 26, 2020
Genetic and gene expression studies implicate renin and endothelin-1 in edema caused by peroxisome
William J Geese1, William Achanzar, Cindy Rubin
1R and D, Bristol Myers Squibb Co, Princeton, New Jersey 08543-5400, USA. william.geese@bms.com
Objective:
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists can cause peripheral edema in susceptible individuals. To investigate the mechanistic basis underlying this adverse event, we performed a candidate gene analysis of patients enrolled in clinical trials of muraglitazar, an investigational PPARalpha/gamma dual agonist, and developed a cell culture-based gene expression assay and nonhuman primate model of edema to study the edemagenic properties of PPARgamma agonists.
Methods:
A total of 213 single nucleotide polymorphisms (SNPs) in 63 genes were genotyped in 730 participants. Chi-square and logistic regression analyses were used to test for association with edema. Transcriptional responses to PPARgamma agonists were evaluated in Calu-6 cells using quantitative real-time PCR. Male Cynomolgus monkeys were treated with PPAR agonists and were evaluated for edema using MRI.
Results:
SNPs in renin (rs2368564) and endothelin-1 (rs5370) were associated with reduced risk of edema (P=0.003 and P=0.028, respectively) and an SNP in beta1 adrenergic receptor (rs1801253) was associated with increased susceptibility to edema (P=0.034). Gene expression studies revealed that renin and endothelin-1 were regulated by PPARgamma in Calu-6 cells. A survey of 10 PPARgamma agonists further revealed that a compound's in vitro potency was correlated with its edemagenic potential leading to the prediction that one of three previously uncharacterized PPARgamma agonists would cause less edema. This prediction was validated in a nonhuman primate model of PPARgamma agonist-induced edema.
Conclusion:
Our results implicate a key role for renin and endothelin-1 in the edema caused by PPARgamma agonists and demonstrate how knowledge gained from pharmacogenetic studies can be applied in drug discovery.
Insights
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists can cause edema. Genetic variations in renin and endothelin-1 influence edema risk, providing insights for safer drug development.
Area of Science:
- Pharmacology and Genetics
- Cardiovascular Research
- Drug Discovery
Background:
- Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are known to induce peripheral edema in some patients.
- The precise mechanisms underlying PPARgamma agonist-induced edema are not fully understood.
- Investigating genetic factors and molecular pathways is crucial for understanding and mitigating this adverse drug reaction.
Purpose of the Study:
- To elucidate the genetic and molecular basis of peripheral edema associated with PPARgamma agonists.
- To identify genetic markers predictive of edema risk in patients treated with PPARgamma agonists.
- To develop and validate preclinical models for studying PPARgamma agonist-induced edema.
Main Methods:
- Candidate gene analysis of 730 participants in clinical trials, genotyping 213 single nucleotide polymorphisms (SNPs) in 63 genes.
- Gene expression analysis in Calu-6 cells to assess transcriptional responses to PPARgamma agonists.
- Edema evaluation in a nonhuman primate model treated with PPAR agonists and assessed via MRI.
Main Results:
- Specific SNPs in renin (rs2368564) and endothelin-1 (rs5370) were associated with a reduced risk of edema.
- An SNP in the beta1 adrenergic receptor (rs1801253) was linked to increased susceptibility to edema.
- In vitro studies confirmed PPARgamma regulation of renin and endothelin-1; compound potency correlated with edemagenic potential, validated in a primate model.
Conclusions:
- Renin and endothelin-1 play a significant role in PPARgamma agonist-induced edema.
- Pharmacogenetic findings can be effectively applied to enhance drug discovery and development processes.
- This study provides a framework for predicting and potentially preventing drug-induced edema.
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