# Targeting immune dysfunction during transition from AKI to CKD

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $368,500

## Abstract

Project Summary
Acute kidney injury (AKI) significantly increases the risk of developing progressive kidney fibrosis and chronic
kidney disease (CKD). T cells and polymorphonuclear neutrophils (PMNs) have been shown involved in
pathogenesis of AKI; however, their role(s) during AKI-to-CKD transition remain uncertain. Our recent
publication and preliminary data revealed that failure of resolving tubular injury from unilateral
ischemia/reperfusion injury (U-IRI, a rapid AKI-to-CKD transition mouse model) led to not only macrophage
persistence but also a second wave of T cells and PMNs infiltrating into tubulointerstitium, which closely
associated with a proinflammatory milieu. Concomitantly, the tubular cells from U-IRI kidney expressed higher
level of injury marker, vascular cell adhesion molecule 1 (Vcam1), and exhibited a dedifferentiated expression
profile, correlating with kidney atrophy. Clinically, we found that increasing numbers of T cells and PMNs in the
renal interstitium at the time of renal biopsy in patients with AKI negatively correlated with 6-month recovery of
GFR. In the U-IRI mouse model, we found that depletion of T cells and PMNs attenuated the second wave of
tubular injury and partially restore tubule mass, suggesting that T cells and PMNs promote secondary tubular
injury and kidney atrophy, and that blocking T cells and PMNs recruitment can attenuate CKD from AKI. Our
chemokine/receptor pair analyses from the scRNA-seq dataset on the IRI kidneys identified that CXCL16 and
MCP-2 (Ccl8) are the top homing signals to recruit T cells (CXCR6+) and PMNs (CCR1+) and that persisted
macrophages are the primary source of CXCL16 and MCP-2 during AKI-to-CKD transition. Together, these
findings have led us to hypothesize that in the setting of failed tubular repair, macrophage-expression of
CXCL16 and MCP-2 promotes a second wave of T cells and PMNs infiltrating into the injured kidneys and that
tubular VCAM-1 enhances T cells adhesion and retention, which together lead to secondary tubular injury.
Thus, targeting the CXCL16/CXCR6 and MCP-2/CCR1 as well as VCAM-1/T cell signaling after kidney injury
holds great potential for the treatment of CKD progression. To test this hypothesis, we propose to define the
importance of CXCL16/CXCR6 and VCAM-1 signaling in T cell homing and adhesion (SA1) and the
importance of MCP-2/CCR1 signaling in PMN homing (SA2) during AKI-to-CKD transition and then to translate
our understanding of these homing signals into developing polyamidoamine dendrimer nanoparticles that can
selectively deliver siRNAs to knockdown these homing signals to slow or even prevent CKD progression (SA3).
This work will provide preclinical data defining how to prevent the second wave of immune activation and
transition from AKI to CKD.

## Key facts

- **NIH application ID:** 10636189
- **Project number:** 1R01DK135689-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Leyuan Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $368,500
- **Award type:** 1
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10636189

## Citation

> US National Institutes of Health, RePORTER application 10636189, Targeting immune dysfunction during transition from AKI to CKD (1R01DK135689-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10636189. Licensed CC0.

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