# Protein Kinase A (PKA) Signaling in the Cystogenesis and Dedifferentiation of Proximal Tubules

> **NIH NIH SC2** · TUSKEGEE UNIVERSITY · 2020 · $147,000

## Abstract

Project Summary
Autosomal dominant polycystic kidney disease (ADPKD) affects more than 600,000 people in the USA and is
caused by mutations primarily in genes PKD1 and PKD2. In ADPKD, cysts and fibrosis replace the renal
parenchyma leading to renal pathology and failure. Currently, in the USA there are no approved therapies to
stop or slow cyst growth. Increased levels of second messenger cAMP is one of the key initial events associated
with PKD mutations. cAMP activates multiple signaling pathways including the Protein Kinase A (PKA) pathway
that results in phosphorylation of transcription factor Creb and other substrates. Cysts may arise from different
tubular segments in PKD such as proximal tubules (PTs) and collecting ducts (CDs). Potential therapies to
modulate cAMP/PKA signaling in CD-derived cysts are under clinical trials however, strategies to control
cAMP/PKA signaling in PT-derived cysts remain largely undefined. Furthermore, early interventions during
childhood to reduce cystic burden have been recommended to preserve maximum renal function. Available data
suggest that PT-derived cysts predominate in the developing kidney. Our recently published studies suggest that
cAMP-mediated PKA activation plays a key role in the cystogenesis of PTs of the developing kidneys. Our
studies also suggest that PKA contributes to the dedifferentiation of PT cystic segments of the developing and
developed kidney, a process known to contribute to cystogenesis. Proximity of PKA to cAMP makes it a suitable
therapeutic target however, the direct role of PKA in PT cystogenesis has not been investigated. The objective
of this proposal is to test the overarching hypothesis that aberrant cAMP/PKA signaling is a key factor driving
PT de-differentiation that promotes cyst formation in the kidney. This hypothesis will be tested in the following
two aims. Aim 1: Examine the direct effect of PKA in the dedifferentiation of PTs in culture. We will determine
whether modulation of PKA activity in in vitro cultures is sufficient and/or necessary for PT dedifferentiation as
an early step to cystogenesis. Aim 2: Determine the effects of constitutive PKA activation on the cystogenesis
and dedifferentiation of PTs in vivo. We will determine whether constitutive activation of PKA in differentiated
PTs is sufficient to induce their de-differentiation, leading to cystogenesis as well as initiate multi-faceted cellular
responses such as fibrosis and inflammation-associated changes from the surrounding renal parenchyma.
These studies will define a direct novel role of PKA in the dedifferentiation and cystogenesis of PT and establish
PKA as a potential therapeutic target. These studies will lay the foundation for the future studies that will
determine whether modulation of PKA activity in PTs exacerbates or ameliorates cystogenesis and
dedifferentiation in a PKD mouse model. Future studies will also focus to identify novel substrates of PKA
implicated in the dedifferentiation an...

## Key facts

- **NIH application ID:** 10000947
- **Project number:** 5SC2GM130475-03
- **Recipient organization:** TUSKEGEE UNIVERSITY
- **Principal Investigator:** Pawan Puri
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $147,000
- **Award type:** 5
- **Project period:** 2018-09-12 → 2023-07-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000947

## Citation

> US National Institutes of Health, RePORTER application 10000947, Protein Kinase A (PKA) Signaling in the Cystogenesis and Dedifferentiation of Proximal Tubules (5SC2GM130475-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10000947. Licensed CC0.

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