Kidney Week

Abstract: FR-OR41

Loss of CELF4 in Kidney Dorsal Root Ganglion Neurons Leads to Acute Onset of Glomerular Diseases

Session Information

• Glomerular Diseases: Mechanisms and More
  October 25, 2024 | Location: Room 1, Convention Center
  Abstract Time: 05:10 PM - 05:20 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Fitzsimons, Lindsey Avery, University of New England, College of Osteopathic Medicine, Biddeford, Maine, United States

Lindsey Avery Fitzsimons, MS, PhD

• Mueth, Madison G., University of Maine, Graduate School of Biomedical Science & Engineering, Orono, Maine, United States

Madison G. Mueth

• Akom, Michael C., Maine Medical Center, Portland, Maine, United States

Michael C. Akom, MD

• Oakley, Grant, Maine Medical Center, Portland, Maine, United States

Grant Oakley, DO

• Harrison, Benjamin James, University of New England, Center for Excellence in Neurosciences, Biddeford, Maine, United States

Benjamin James Harrison, PhD

Background

Sustained upregulation of renal sympathetic and sensory nerve reflexes, known as renorenal hyperreflexia (RRH), promote the onset/ progression of chronic kidney disease (CKD). RRH consequences are exacerbated with the onset of inflammation and secretion of trophic factors (e.g. nerve growth factor; NGF), previously shown to promote structural and functional damage to the glomerulus. Our preliminary data demonstrate that pathogenic activation of peripheral sensory nerve fibers is controlled by an RNA binding protein, known as CUGBP Elav-Like Family Member 4 (CELF4). The goal of this study was to investigate the role of CELF4 as a tonic regulator of renal DRG neuron (RDN) excitability, RRH and overall kidney function.

Methods

An inducible, CGRP^cre mouse was used to direct Celf4-knockout (KO) from adult sensory neurons, followed by behavior assessments of peripheral neuropathy, RDN electrophysiology, semiquantitative blood and urinalysis and histopathological analyses of kidney and glomerular cytostructure.

Results

Celf4 KO mice displayed robust hind-paw hypersensitivity to mechanical and thermal stimuli that was further exacerbated with NGF injection. Patch-clamp recordings confirmed acutely-dissociated, capsaicin-sensitive RDN become hyperexcitable following Celf4 KO. Immunofluorescence confirmed coexpression of CGRP, TRPV1 and CELF4 in RDN. Celf4 KO kidneys displayed hydronephrosis and increased pre-fixation weight and semi-quantitative urinalysis revealed Celf4 KO mice develop 2-3+ proteinuria and microscopic hematuria. Histological analyses with H&E, PAS and PAS-silver stained kidney sections revealed a novel and unexpected renal phenotype in Celf4 KO, characterized by pronounced mesangial expansion, extracellular matrix deposition, hypercellularity and incidence of glomerular sclerosis. When combined, these findings suggest a Celf4 KO renal phenotype that is consistent with membranoproliferative glomerulonephritis (MPGN).

Conclusion

We demonstrate that CELF4 is co-expressed with TRPV1 in CGRP+ RDN, and that loss of CELF4 increases neural excitability and sensitivity of RDN, leading to development of MPGN. These data represent preliminary data from ongoing studies in our lab investigating CELF4 as a possible protective regulator against RRH mechanisms responsible for impairing renal/glomerular function in hypertension and CKD.

Funding

• Other NIH Support