# Long-term effects of acute renal failure

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $545,742

## Abstract

Acute kidney injury (AKI) is a significant factor predisposing chronic kidney disease (CKD), however the factors
mediating CKD progression are not clear. T-helper 17 cells (Th17) represent a primary lymphocyte population
and may play a central role in coordinating immune and renal cell activity in AKI and subsequent CKD induced
by exposure to high salt diet. Studies from the recent project period demonstrated that impairment of IL17
activity attenuates both AKI and progression of CKD and hypertension. We also demonstrated the dependence
of Th17 activity on the store-operated calcium channel, Orai1. However, there remains important questions
regarding Th17 effects on AKI and CKD. First, the phenotype Th17 cells at different stages of AKI or CKD is
not known; second, the physiological regulatory factors modulate Th17 reactivation associated with CKD are
not defined; third, the effect of Th17 activity on the variety of potential renal cell targets is incompletely
defined. We hypothesize that the dynamic regulation of Th17 cells plays a central role in the development of
kidney injury, repair and progression to chronic kidney disease. We propose that Ca2+ signaling stimulated by
high-salt diet increases the pathogenicity of Th17 cells by changing their cytokine profile, and further propose
that the pleiotropic activity Th17 cytokines such as IL17A and GM-CSF alters parenchymal, innate, and
adaptive immune cell function to promote kidney injury. Aim 1 of the proposal will utilize IL17A reporter mice
to more completely define the phenotype and localization of Th17 cells using FACS, imaging tissue cytometry
and evaluate spatial distribution of Th17 with developing tertiary lymphoid structures (TLS). A Th17 fate-
tracing model will be used to characterize whether quiescent Th17 cells following recovery from AKI, express
the Orai1- Ca2+ channel, contribute T-memory populations, differentiate to other T-helper populations, or are
essential for the reactivation of Th17 cells during progression of CKD. Finally, we will determine if inhibition of
these pathways using an FDA approved SOCC blocker following the establishment of AKI during the recovery
phase, impairs the secondary activation of Th17 cells associated with progression of CKD. In aim 2, we will
expand studies to define alterations in the transcriptional signature of Th17 cells during progressive CKD
induced by high salt diet. In addition, we will determine how inhibition of the Th17 pathway by pharmacological
and gene knockout approaches affects immune and renal cell transcriptional responses to injury and
investigate specific alterations in B-cells and formation of TLS. Finally, we will examine the potential
contribution of GM-CSF, a factor co-secreted byTh17 cells, during AK and the AKI to CKD transition.

## Key facts

- **NIH application ID:** 10882650
- **Project number:** 2R01DK063114-19A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** David P. Basile
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $545,742
- **Award type:** 2
- **Project period:** 2003-07-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882650

## Citation

> US National Institutes of Health, RePORTER application 10882650, Long-term effects of acute renal failure (2R01DK063114-19A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10882650. Licensed CC0.

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