# The role of cyclin G1 in chronic kidney disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $382,500

## Abstract

Acute kidney injury (AKI) is not only an independent risk factor for increased mortality in hospitalized patients, it
dramatically increases the likelihood of developing chronic kidney disease (CKD) later in life. Treatment
options to prevent the AKI to CKD transition, as well as CKD progression to end-stage kidney disease, remain
very limited. It is known that cell cycle arrest at the G2/M phase contributes to progressive kidney fibrosis;
however, the underlying mechanism is unclear. Our preliminary data have identified cyclin G1, an atypical
cyclin, as a novel regulator of G2/M arrest in the kidney. Cyclin G1 is not expressed in uninjured kidney and is
not required for cell cycle progression. Cyclin G1 is dramatically upregulated in mouse models of chronic
kidney disease. Deletion of cyclin G1 inhibits G2/M arrest and fibrosis progression in models of CKD. We have
identified cyclin G1’s cyclin dependent kinase (CDK5) as the main driver of G2/M arrest and fibrosis in CKD.
Our hypothesis is cyclin G1 induces a pro-fibrotic G2/M arrest via activation of CDK5, contributing to
fibrosis by promoting a pathological mitochondrial fragmentation and senescence-like secretory
phenotype. The aims of the application are to (1) Define the mechanism by which cyclin G1 induces G2/M
arrest; (2) Determine the role of cell cycle-dependent changes to mitochondria in fibrosis progression; and (3)
Define how G2/M arrest drives secretion of profibrotic factors. In Aim 1, we will test if chronic injury to the
kidneys is reduced in mice lacking CDK5 and define how cyclin G1/CDK5 regulates G2/M arrest, profibrotic
cytokine production and organ fibrosis. For Aim 2, we will utilize in vitro cell culture knockout models, specific
inhibitors and molecular biology approaches to assess if disruption of the mitochondrial network, which occurs
during the G2 and M phases of the cell cycle, leads to profibrotic phenotypes during prolonged mitochondrial
fragmentation observed in G2/M arrested cells. We will also quantify changes in mitochondrial morphology in
vivo using a novel super-resolution imaging technique developed in our lab. In Aim 3 we will examine whether
the CDK5 induce senescence-like phenotypes can promote cytokine secretion from proximal tubular cells.
Successful completion of the aims will establish the role of cyclin G1 in organ fibrosis as well as determine the
mechanism by which G2/M arrest regulates fibrotic responses, informing the potential therapeutic potential of
inhibition of cyclin G1. Anti-cyclin G1 gene therapy has been approved for phase 3 clinical trials and used in
patients with solid tumors, with up to 9-year follow-up. Thus, targeting of cyclin G1 represents a promising
approach to treat fibrosis.

## Key facts

- **NIH application ID:** 9884760
- **Project number:** 5R01DK121101-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Craig Robert Brooks
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884760

## Citation

> US National Institutes of Health, RePORTER application 9884760, The role of cyclin G1 in chronic kidney disease (5R01DK121101-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9884760. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*