# DACH1 transcriptomic regulation of glucocorticoid-responsive glomerular disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $372,900

## Abstract

Project Summary:
Podocyte injury is the causative event in all proteinuric kidney diseases including minimal change disease
(MCD) and FSGS. Glucocorticoids (GCs) are often the initial and preferred treatment for these conditions. The
beneficial effects of GCs are not caused by immunomodulation, but are mediated by their direct effects on
podocytes. Unfortunately, GC therapy is riddled with severe systemic toxicities that limit their use. Identification
of essential salutary GC-induced targets in podocytes might allow for new therapeutic approaches that can
minimize toxicity but maintain efficacy. In the current proposal, we identified diminished expression of the
transcription factor dachshund1 (DACH1) in a large-scale mutagenic screen designed to identify mutations that
restored injury susceptibility to genetically injury-resistant podocytes. We found DACH1 to be essential to
podocyte function in both novel global and podocyte-specific knock out mouse models. Importantly, podocyte-
specific DACH1 heterozygous mice, which have reduced glomerular DACH1 expression levels similar to
human MCD and FSGS patients, were remarkably susceptible to adriamycin nephropathy, and this phenotype
was ameliorated by GC therapy. We found that GC administration caused early and significant induction of
DACH1 expression, and we confirm binding of GC receptor to the DACH1 promoter by ChIP assay. Moreover,
the protective allele of a DACH1 intronic SNP (rs626277), which has been identified in genome-wide
association studies as linked to incident and prevalent CKD, introduced a GC-alpha transcription factor-binding
site that was abrogated in the presence of the risk allele. When we tested these alleles in reporter studies, the
protective allele dramatically augmented DACH1 promoter activity in response to GCs, consistent with GC-
potentiated enhancer function. In GC treated kidney transplant patients, the protective rs626277 allele
correlated closely with increased glomerular DACH1 expression and improvement in proteinuria. Furthermore,
in a cohort of MCD and FSGS patients, protective and risk alleles correlated with GC responsiveness and
resistance respectively. We hypothesize that DACH1 is a central transcriptomic regulator of the salutary
glomerular GC response and that rs626277 genotype status, which modulates podocyte DACH1 transcription
in the setting of GC therapy, is an important determinant of GC-responsiveness in nephrotic syndrome
patients. Our proposal includes three specific aims: i) demonstrate that DACH1 over-expression is protective
using a novel inducible podocyte-specific DACH1 transgenic mouse model ii) show that the beneficial effects of
GCs in podocytes are mitigated in the absence of DACH1 expression using novel inducible podocyte-specific
knockout mice iii) correlate rs626277 genotype status with clinical outcomes in GC-treated MCD and FSGS
patients in NEPTUNE and cross-examine mechanistic and transcriptomic data obtained from the first two aims
i...

## Key facts

- **NIH application ID:** 10126845
- **Project number:** 5R01DK121978-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Lewis Kaufman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,900
- **Award type:** 5
- **Project period:** 2020-03-12 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126845

## Citation

> US National Institutes of Health, RePORTER application 10126845, DACH1 transcriptomic regulation of glucocorticoid-responsive glomerular disease (5R01DK121978-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10126845. Licensed CC0.

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