Krish Patel
Pronouns: he/him
Research Mentor(s): Matthias Wolf
Research Mentor School/College/Department: Pediatrics / Medicine
Program:
Authors: Krish Patel, Ingrid Apel, Huiyuan Wu, Sung Wan An, Matthias Wolf
Session: Session 5: 2:40 pm – 3:30 pm
Poster: 75
Abstract
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an inherited kidney disease which is due to pathologic variants in five genes. The majority of patients have a heterozygous pathogenic variant in the Uromodulin gene. This variant gene causes misfolding of the Uromodulin protein, which results in intracellular Uromodulin accumulation, leading subsequently to apoptosis, kidney fibrosis, and failure. There is no therapy available for patients with ADTKD. In this study, we have screened 1,400 FDA-approved drugs by applying a cell-based assay. The assay consists of stable transfected kidney cells containing the luciferase-tagged mutant Uromodulin. We screened for FDA-approved compounds enhancing the luciferase signal in the culture medium suggesting improved secretion of mutant Uromodulin. In this screen, we identified the mineralocorticoid receptor antagonist spironolactone as a candidate to enhance mutant Uromodulin secretion. So far, spironolactone is used in kidney diseases to improve hypertension and proteinuria. This project wants to confirm the effect of spironolactone on mutant Uromodulin applying counter screening for cell viability and apoptosis. Additionally, it remains unclear how blocking the mineralocorticoid receptor induces more efficient mutant Uromodulin secretion. We will investigate if the mineralocorticoid receptor is expressed in MDCK and HEK293 cells which were used for our screen and counter screen. Furthermore, we will investigate the effect of other mineralocorticoid receptor antagonists on mutant Uromodulin secretion. If the effect of Spironolactone is independent of the mineralocorticoid receptor, we will also investigate other potential pathways by mRNA seq. Candidate pathways will be confirmed by applying qPCR and Western blotting. The goal of our research is to confirm the beneficial effect of spironolactone on mutant Uromodulin secretion in vitro and to better understand the molecular mechanism of how spironolactone may stimulate mutant Uromodulin secretion. Spironolactone may provide a therapeutic bridge for patients with ADTKD to reduce the need for dialysis and kidney transplants until a more efficient new small molecule will be available.
