Kidney Week

Abstract: FR-PO635

Neuroinflammation in Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Mechanisms and Models
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Klawitter, Jelena, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Jelena Klawitter, PhD

• Wheeler, Garrett B., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Garrett B. Wheeler

• Hopp, Katharina, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Katharina Hopp, PhD

• Klawitter, Jost, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Jost Klawitter, PhD

• Christians, Uwe, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Uwe Christians, DrMed

Background

The incidence of intracranial aneurysms (IA) in patients with autosomal dominant polycystic kidney disease (ADPKD) is three- to four-times higher than that in the general population. Inflammation plays a key role in the development of IA and their rupture. Systemic inflammation and associated metabolic changes in the kidney are well described in ADPKD. However, the presented results describe, for the first time, the inflammation-related alterations and metabolic derangements in the brains of animals with PKD.

Methods

Brains (cortex and hippocampus) were collected from 6-mo old WT and Pkd1^RC/RC (orthologous ADPKD model) mice. Proteome Profiler Mouse cytokine arrays, in conjunction with Western blot and confocal microcopy analyses, were used to assess the degree of neuroinflammation. Mass spectrometry-based metabolomics was used to assess the metabolic changes and the levels of oxidative stress.

Results

Accumulation of multiple proinflammatory proteins including several interleukins, C-reactive protein, RANTES, and Vascular Cell Adhesion Protein 1 (VCAM1) was observed in brains of both sexes of Pkd1^RC/RC mice. This was accompanied by astrocyte (GFAP⁺) and microglia (Iba1⁺) activation. Protective cytokines such as Chemerin were downregulated in brains of Pkd1^RC/RC mice.
Metabolically, Pkd1^RC/RC mice presented with decreased brain levels of multiple energy-supplying amino acids (ARG, LEU, ASP). TRP metabolism via kynurenine pathway was increased resulting in lower TRP availability and serotonin production. We also observed an accumulation of several uremic toxins (indoxyl- and p-cresyl sulfate) and oxidative stress markers in PKD mice. The accumulation of these uremic toxins has been shown to directly associate with increased blood-brain barrier (BBB) permeability. Together with kynurenines, they bind to aryl hydrocarbon receptor (AhR), that regulates vascular homeostasis and integrity, and whose expression we confirmed to be higher in Pkd1^RC/RC brains.

Conclusion

We show that neuroinflammation is present in the brains of Pkd1^RC/RC mice. Genetic polycystin deficiency and increased systemic inflammation lead to a disruption of BBB resulting in an accumulation of uremic toxins, increased oxidative stress and derangements in cellular metabolism. Increased expression of VCAM1 and AhR could further contribute to the vessel modulation and IA pathology.