# Long-term effects of acute renal failure

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $489,836

## Abstract

Acute kidney injury (AKI) is a significant factor predisposing chronic kidney disease (CKD), however the factors
mediating CKD progression are not clear. Work from the previous project period identified T-helper 17 cells
(Th-17) as a primary lymphocyte population activated by AKI and further demonstrated that it is strongly
activated by exposure of post AKI rats to high salt diet. Recent preliminary data indicate a potential role for
altered lymphocyte intracellular calcium signaling in mediating enhanced IL17 activity. The overarching
hypothesis to be tested is that AKI results in persistent IL-17 activity from CD4+ cells and this
activity is integral to the subsequent development of CKD. As such, Specific aim 1 of this
application will investigate the role of Th-17 cells in the mediation of the AKI to CKD transition in rats. The
studies will utilize a rat model of AKI-to CKD established in our laboratory. Two approaches will be used to
inhibit Th17 activity. In one series of studies, we will use an antibody-based approach to block IL17 activity in
rats in vivo. Additional studies will utilize a transgenic rat in which the RORᵞT gene has been mutated. This rat
shows impaired activation of Th-17 cells following AKI and lymphocytes obtained from these rats show an
impaired IL17 responses in vitro. Using either approach we will test whether Th17 cells activated by elevated
dietary salt following recovery from AKI participate in the processes of renal fibrosis, sodium sensitive
hypertension, altered vascular reactivity and distant organ injury following AKI Specific aim 2 of this
application will more precisely examine altered lymphocyte signaling associated with IL17. Isolated
lymphocytes from normal or post AKI rats will be stimulated in vitro (by elevated Na+ and Ang II) for enhanced
IL17 synthesis. The goal of these studies will be to determine how prolonged enhanced IL17 responses to are
retained in CD4 cells following resolution of renal injury. We will also investigate potential physiologically
relevant mediators that may activate these responses in vivo. Additional studies in this aim will investigate
contribution of the store-operated Ca++ Oria1 to altered Ca signaling and the IL17 response. Finally studies in
this aim will seek to investigate the effect of in vivo inhibition of Oria-1 on the activation of Th-17 cells and the
AKI to CKD transition. Specific aim 3 will determine whether activation of Th17 cells may underlie the AKI to
CKD transition in human patients. These studies will utilize samples available from the ASSESS-AKI
consortium which has collected samples from AKI patients for up to 4 years following hospital discharge. We
will compare circulating Th17 cytokines as an initial step to determine the activity of this pathway in patients
with AKI who progress versus patients who recovery renal function as well as control patients.

## Key facts

- **NIH application ID:** 9976522
- **Project number:** 5R01DK063114-17
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** David P. Basile
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,836
- **Award type:** 5
- **Project period:** 2003-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976522

## Citation

> US National Institutes of Health, RePORTER application 9976522, Long-term effects of acute renal failure (5R01DK063114-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976522. Licensed CC0.

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