# AKAP Modulation of Renal Signaling

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $340,937

## Abstract

ABSTRACT
A-Kinase Anchoring Proteins (AKAPs) organize second messenger responsive enzymes to direct the flow of
information within cells. These proteins were initially discovered as protein kinase A (PKA) binding partners.
However, it is now clear that the primary function of AKAPs is to integrate a variety of intracellular signals. This
occurs by sequestering PKA with other kinases, small GTPases, and protein phosphatases within range of
their substrates. The physiological significance of this mechanism has been validated in several contexts. This
proposal exploits new discoveries about AKAP220 signaling complexes to establish if manipulation of
this macromolecular assembly is of therapeutic value in the restoration of water homeostasis to
manage aspects of autosomal dominant polycystic kidney disease.
Human kidneys filter about 180 liters of fluid every day, yet a majority of the water is reabsorbed, as only 1.5
liters of urine is excreted. Urine is concentrated in the kidney-collecting duct where water is reabsorbed from
luminal fluid through aquaporin-2 (AQP2) water pores. The hormone arginine vasopressin (AVP) increases
water permeability by inducing PKA phosphorylation of Ser256 on AQP2 to stimulate translocation of the water
pore from vesicles to apical membranes of collecting ducts. Not surprisingly, defects in aquaporin-2
trafficking have dire pathophysiological consequences.
Polycystic kidney disease occurs when fluid filled cysts grow in the kidney collecting ducts. These cysts
eventually replace much of the kidneys and lead to kidney failure. Autosomal dominant polycystic kidney
disease is a leading cause of end-stage renal failure worldwide. At the molecular level, mutations in the cilia
transmembrane proteins polycystin 1 (PC1) and polycystin 2 (PC2) promote defective osmoregulation through
aquaporin-2. Aberrant cAMP signaling, altered cilia assembly and reduced Rho GTPase activity further
contribute to the expansion of fluid filled cysts. Our preliminary findings implicate AKAP220-binding
partners in each of these pathological responses.
An experimental plan of three specific aims is proposed. Aim 1 will employ state-of-the-art analytical and
proximity ligation approaches to define the enzyme composition, stoichiometry and subcellular location of
AKAP220 complexes. Aim 2 will investigate 3D organoid cultures to establish if AKAP220-associated GTPase
effector protein IQGAP1 sustains actin barrier formation through local modulation of RhoA. Aim 3 will employ
drug delivery to CRISPR/Cas 9 gene-edited kidney-derived cells in a microfluidic “Kidney-on-a-chip” device to
determine if AKAP220-associated phosphatase 1 (PP1) impacts signaling events that underlie aquaporin-2
trafficking and cilia biogenesis.

## Key facts

- **NIH application ID:** 10409644
- **Project number:** 5R01DK119186-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** John D Scott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $340,937
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409644

## Citation

> US National Institutes of Health, RePORTER application 10409644, AKAP Modulation of Renal Signaling (5R01DK119186-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10409644. Licensed CC0.

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