Kidney Week

Abstract: TH-PO0292

Podocyte-Derived Acetylcholine Protects from FSGS by Preserving Podocyte Structure

Session Information

• Glomerular Diseases: Cell Biology
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Garcia, Gabriela E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Gabriela E. Garcia, MD

• Roncal-Jimenez, Carlos Alberto, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Carlos Alberto Roncal-Jimenez, MS, MSc

• Fornoni, Alessia, University of Miami Miller School of Medicine, Miami, Florida, United States

Alessia Fornoni, MD, PhD, FASN

• Chonchol, Michel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Michel Chonchol, MD, FASN

• Johnson, Richard J., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Richard J. Johnson, MD

• Truong, Luan D., Houston Methodist Hospital, Houston, Texas, United States

Luan D. Truong, MD

Background

Podocyte injury is the earliest morphologic feature of FSGS and is often accompanied by changes in cytoskeletal proteins that lead to effacement of the podocyte foot processes.
While acetylcholine is traditionally known as a neurotransmitter, it is also expressed by non-neuronal cells. Notably, non-neuronal acetylcholine regulates basic cell functions, such as mitosis, cell differentiation, organization of the cytoskeleton, and cell–cell contact.

Methods

Using ChAT(BAC)-EGFP transgenic mice (ChAT mice), which express enhanced green fluorescent protein (EGFP) under the control of transcriptional regulatory elements for choline acetyltransferase (ChAT), we found that acetylcholine is produced by the podocyte. Here we investigated if podocyte acetylcholine could act in an autocrine manner via the activation of the expressed acetylcholine receptors in podocytes to protect against FSGS.

Results

Experimental studies in ChAT mice revealed that podocyte ChAT expression and acetylcholine production are increased in adriamycin-induced nephropathy, the prototypical experimental model of primary FSGS. Furthermore, upregulating ChAT attenuates kidney injury, reduces proteinuria, and preserves podocyte structure. In contrast, podocyte-specific ChAT knockout mice exhibit more severe kidney damage following adriamycin administration. Mechanistically, we found that acetylcholine plays a key role in regulating podocytes morphology through muscarinic acetylcholine receptors (mAChRs) by inducing myosin regulatory light chain phosphorylation (pMRLC) that modulates the activity of nonmuscular myosin II (NMII) which is critical in the control of cell shape, cell adhesion, and cell migration. This phosphorylation is reduced by blocking the effect of mAChRs with atropine. Importantly, we found that ChAT expression/acetylcholine production can be induced in podocytes in vivo with clinically approved drugs.

Conclusion

These studies support a role for podocyte-derived acetylcholine as an important endogenous protective factor, which can be regulated, and provide insights into new nonimmunosuppressive therapeutic approaches for glomerular disease.

Acknowledgment

This work was supported in part by National Institute of Health DK138929 (G.E.G.),

Funding

• NIDDK Support