# Targeting heat shock protein 72 to improve renal function after transplantation

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2021 · $514,920

## Abstract

PROJECT SUMMARY ABSTRACT
 Long-term allograft function tends to be poor for people who receive kidneys from deceased donors, which
comprise 70% of total transplants. A key contributor to these poor outcomes is cold storage (CS) of the organs,
which induces injury during preservation. Accordingly, there is an urgent need to understand the mechanisms
by which CS activates molecular pathways that induce renal damage in the recipient. Our long-term goal is to
identify these CS-related pathways and apply targeted therapies during CS to improve outcomes and decrease
transplant-associated mortality. One of the important molecular determinants of CS-induced kidney injury is
abnormal protein homeostasis. During stress, heat-shock proteins and the proteasome play a concerted role in
maintaining protein homeostasis. Hsp72 is the major stress-inducible homologue of Hsc70, the cognate member
of the heat-shock protein 70 family that exhibits housekeeping function in all nucleated cells and is necessary
for cell survival. Importantly, Hsc70 and Hsp72 play critical roles by binding damaged proteins and recruiting the
proteasome for targeted degradation, preventing the nonspecific aggregation of damaged proteins. In addition
to its protective roles, Hsp72 is implicated in the pathogenesis of numerous human diseases by modulating the
immune system and inflammation. Using a clinically relevant rat model of renal CS combined with
transplantation, we showed that CS decreases proteasome function and impairs protein homeostasis in the
transplants. How CS decreases proteasome function in the transplants is not known. We hypothesize that CS-
mediated activation of HSF1 and p38MAPK mediate the upregulation of Hsp72 and phosphorylation of Rpt6,
leading to proteasome dysfunction and injury after transplantation. We have preliminary data supporting this
hypothesis. We have also established animal models of CS/transplantation, which mimic the clinical reality more
effectively than simple CS/warm perfusion and will allow us to test our hypothesis through 3 specific aims. Aim
1: Define the mechanism of Hsp72 upregulation and its impact on proteasome dysfunction during renal CS and
transplantation. Aim 2: Delineate the mechanism of Rpt6 phosphorylation/aggregation and its impact on
proteasome dysfunction during renal CS and transplantation. Aim 3: Determine the therapeutic utility of the
Hsp72 inhibitor HS-72 using both rat and human models of renal CS and transplantation. This project uses a
clinically relevant rat kidney transplant model as well as ex vivo human kidney perfusion pump to test the effects
of novel CS-based therapies (e.g., HS-72) on proteasome/renal function after transplantation. We expect to
identify molecular mediators of proteasome dysfunction and renal injury following CS and transplantation. These
findings would be readily translatable, such as by administering drugs targeting these pathways to the CS
solution to improve transplant outcomes and reduce mort...

## Key facts

- **NIH application ID:** 10209484
- **Project number:** 1R01DK123264-01A1
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Nirmala Parajuli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $514,920
- **Award type:** 1
- **Project period:** 2021-03-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209484

## Citation

> US National Institutes of Health, RePORTER application 10209484, Targeting heat shock protein 72 to improve renal function after transplantation (1R01DK123264-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10209484. Licensed CC0.

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