# Intra-renal T-cell heterogeneity in ADPKD patients

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2021 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic kidney diseases (CKD) are among the most significant public health problems with an aggregate
prevalence of ~15% and virtually no curative therapies. The most promising group of disorders that may allow
identification of urgently needed CKD drug targets are those with a known underlying molecular defect. Among
them, the most prevalent and most commonly leading to end-stage renal disease (ESRD) is autosomal dominant
polycystic kidney disease (ADPKD; 600,000 patients in the US; the fourth leading cause of ESRD). Because the
diagnosis cannot be excluded until age 40, many ADPKD patients are veterans. While mechanisms that trigger
or promote the pathogenesis of ADPKD are not yet completely understood, we and others have pointed to
specific renal immune cells as key outcome regulators of renal cystic disorders in mice. Our preliminary data
show that these renal immune cells include T-cells, a common renal immune cell type, and recently defined sub-
populations of renal mononuclear phagocytes/macrophages (MP) that control the activity of specific T-cell sub-
lineages. These T-cells, in turn, secrete factors that promote recruitment/differentiation of MPs. As our additional
preliminary data suggest, this positive feedback loop can be triggered or enhanced by specific intra-cystic
microbiota that promote the activity of specific T-cell sub-lineages. Disruption of this feedback loop at the level
of MPs or lymphocytic lineage attenuates renal cystogenesis in mouse models. Therefore, this pathway
represents an attractive therapeutic target. However, several critical gaps in knowledge must be addressed first,
e.g., to establish a causal relationship between microbiota, abnormal T-cell responses in cystic kidneys and
relevance of this concept to human ADPKD patients. The objective of the proposed studies is to address these
limitations by interventional studies in a mouse model and by validating this concept in ADPKD patients. Together
our preliminary studies support a model in which distinct evolutionarily-conserved inter-cellular signaling
networks regulate intra-renal T-cell functional diversification that, in turn, controls epithelial differentiation
abnormalities that enhance ADPKD progression. We will test the relevance of this model to ADPKD patients in
three inter-related aims: i) Test the hypothesis that reduction of microbiota-stimulating effects on Th17 cells
attenuates renal cystogenesis in mice; ii) Test the hypothesis that enhancement of Th17 activity by specific
bacterial species exacerbates renal cystogenesis in mice; iii) Test the hypothesis that plasma or urinary markers
of abnormal Th17 activity correlate with rate of renal cyst growth and predict renal function loss in ADPKD
patients. Accomplishing the goals of this project will allow us to apply the wealth of genetic and cellular
information obtained from the functional counterparts in mouse studies to human patients, provide a means for
a more accurate as...

## Key facts

- **NIH application ID:** 10044403
- **Project number:** 5I01BX004232-02
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Michal Mrug
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044403

## Citation

> US National Institutes of Health, RePORTER application 10044403, Intra-renal T-cell heterogeneity in ADPKD patients (5I01BX004232-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10044403. Licensed CC0.

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