# The Exocyst in Ciliogenesis and Acute Kidney Injury

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2020 · —

## Abstract

Acute kidney injury (AKI) is a significant and increasing problem. Medical management currently consists of
supportive care, with dialysis implemented for the most severe cases; however, morbidity and mortality remain
very high. A major reason for the lack of available treatments for AKI is a gap in the knowledge of how kidney
tubule cells recover from AKI, which has, therefore, limited possible approaches for treatment. Identifying, a
therapeutic target and pathway would meet a major unmet need by allowing for rational drug design. The goal
here is to determine whether the highly conserved eight-protein exocyst trafficking complex, and particularly the
central Sec10 (aka Exoc5) component, can be used to enhance recovery, and/or prevent injury, following AKI.
After renal tubule cell injury, there is initial loss of cell polarity, followed by cell death and sloughing of cells into
the lumen, then spreading and dedifferentiation of viable cells to cover the denuded area, with proliferation,
differentiation, and reestablishment of cell polarity. The polarity, or secretory, pathway is crucial for AKI recovery,
and cell function, and the exocyst is known for mediating the targeting and docking of secretory vesicles carrying
membrane proteins. Over the past twenty years, we showed that the mitogen-activated protein kinase (MAPK)
pathway regulates tubulogenesis. We also showed that the exocyst, especially the Sec10 component, is centrally
involved in renal ciliogenesis and tubulogenesis. Specifically, Sec10 knockdown inhibited, and Sec10
overexpression increased, ciliogenesis and tubulogenesis. These distinct research areas recently converged, as
we showed that Sec10 speeded recovery from oxidative damage, an ischemia-like injury, by activating MAPK.
We have now generated Sec10fl/fl mice, and have preliminary data showing Sec10 deletion in murine proximal
tubules worsens ischemia and reperfusion (I/R) injury, and inhibits repair. Furthermore, site-specific mutation of
the highly-conserved VxPx ciliary targeting sequence in human SEC10 inhibits tubulogenesis in cells grown in
3D collagen gels, and prevents the rescue of sec10 mutant zebrafish. The proposed experiments will test the
overall hypothesis that Sec10 activates the MAPK pathway, through the EGF receptor, to prevent injury
and/or enhance renal recovery following AKI, that this effect is mediated via primary cilia, and that Sec10
is a therapeutic target. Accordingly, we will investigate how Sec10 increases EGF receptor sensitivity, which
activates MAPK to enhance recovery from injury (Aim 1.1). We will then investigate how Sec10 and the exocyst
are involved in mitochondrial function. A critical pathway that has been identified in AKI is alterations in primary
tubular metabolism, which secondarily affect the regional circulation through decreased levels of ATP and
mitochondrial dysfunction. Mitochondria are also involved in ADPKD, the most common ciliopathy, suggesting a
possible link between cili...

## Key facts

- **NIH application ID:** 10016741
- **Project number:** 2I01BX000820-09A1
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** JOSHUA H LIPSCHUTZ
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2011-01-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016741

## Citation

> US National Institutes of Health, RePORTER application 10016741, The Exocyst in Ciliogenesis and Acute Kidney Injury (2I01BX000820-09A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10016741. Licensed CC0.

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