# Genetic Regulation, Tubular Processing and Clinical Relevance of Collecting Duct alpha-Defensins 1-3

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $586,762

## Abstract

PROJECT SUMMARY/ABSTRACT
Vesicoureteral reflux affects 1-2% of all children and up to one third of these patients will experience urinary tract
infections (UTI). The kidney and specifically the collect duct play a critical role in the innate defense of the kidney and
urinary tract. Our group has demonstrated that intercalated cells are the primary source of a wide spectrum of innate
immune antimicrobial peptides. DEFA1A3 (α-defensin 1-3) and its antimicrobial protein (AMP) product, human
neutrophil protein 1-3 (HNP1-3), is important in the innate immune defense of the human kidney. Just this year we have
reported that a) variations in the number of DEFA1A3 DNA copies correlate with UTI susceptibility and antibiotic
response in children with vesicoureteral reflux and UTIs, b) DEFA1A3 mRNA and protein product, HNP1-3 expression is
not limited to leukocytes, but also present in renal collecting duct epithelial cells and c) urine HNP1-3 increase during
UTIs. Our aforementioned findings correlate with the known function of HNP1-3 as an AMP that rapidly destroys
microbes. These finding are important because management of VUR and UTIs is complicated by the current inability to
personalize treatment according to individual risk. For instance if all patients are treated under the assumption of recurrent
pyelonephritis risk, children will be exposed to unnecessary imaging related radiation and antibiotic prophylaxis to
prevent UTIs. Conversely if all patients are treated conservatively, a subset will develop potentially preventable renal
scarring and chronic kidney disease. Further, identification of DEFA1A3 expressed in renal collecting duct cells, raises
the possibility that renal DEFA1A3 expression could be targeted for therapeutics. Because DEFA1A3 DNA copy number
variation is associated with UTI and the recent discovery that renal collecting duct cells express HNP1-3, determining
HNP1-3’s role in the kidney represents clinically relevant research direction. Based on prior publications and preliminary
studies, we hypothesize that renal- and neutrophil-derived DEFA1A3/HNP1-3 have distinct roles in cellular physiology/
pathology and are affected by DNA copy number variations.
To this end, we will identify the unique molecular mechanisms critical to storage, secretion and activation of renally-
derived alpha defensins in humans and murine UTI (Aim 1). We will utilize proteomic techniques using a mouse model
of bone marrow transplantation and urine in children with UTI. In Aim 2, we will use a murine model of kidney
transplantation of a humanized mouse for alpha-defensins to examine the kidney’s role in innate defense against
uropathogens. In Aim 3, we will utilize this murine model and in vitro studies to dissect the role of DNA copy number
variations in the DEFA1A3 locus in UTI susceptibility and antibiotic synergy.

## Key facts

- **NIH application ID:** 9906213
- **Project number:** 5R01DK117934-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Douglas Brock Cines
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,762
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906213

## Citation

> US National Institutes of Health, RePORTER application 9906213, Genetic Regulation, Tubular Processing and Clinical Relevance of Collecting Duct alpha-Defensins 1-3 (5R01DK117934-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9906213. Licensed CC0.

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