Abstract: SA-PO0498
Inflammasome-Independent Role of NLRP3 and ASC in Kidney Inflammation Triggered by Potassium Deficiency
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Komada, Takanori, Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan
- Komori, Satoko, Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan
- Matsumura, Takayoshi, Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan
- Karasawa, Tadayoshi, Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan
- Nagata, Daisuke, Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan
- Takahashi, Masafumi, Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan
Background
Pathological potassium (K+) deficiency causes kidney inflammation and injury, known as hypokalemic nephropathy (HN), the underlying pathogenesis of which is obscure. NLRP3 inflammasomes are platforms that sense the reduction of intracellular K+, engaging inflammation and tissue injury. We investigated whether or not K+ deficiency induces NLRP3 inflammasome-dependent inflammation in HN.
Methods
To evaluate the role of NLRP3 inflammasomes in HN, we analyzed human HN kidney biopsy samples and an experimental HN model of mice fed a low K+ diet. To analyze the contribution of inflammasomes to HN, we used genetic knockout mice of the NLRP3 inflammasome components Nlrp3, Asc, and Casp1/11, as well as ASC-Citrine reporter mice and bone marrow chimera mice. Single-cell RNA sequencing was conducted on non-leukocyte kidney cells from mice fed a normal or low K+ diet. Primary kidney tubular epithelial cells from humans and mice were subjected to in vitro experiments.
Results
Clinically diagnosed HN in humans manifested as upregulation of NLRP3 and ASC in the kidney epithelia. A K+ depletion model in mice demonstrated that kidney-resident NLRP3 and ASC play a key role in triggering early inflammation in the HN kidneys. Unexpectedly, the low-K+-induced kidney inflammation was not dependent on inflammasome activation. A single-cell RNA sequencing analysis revealed ASC upregulation, NF-κB activation, and an increased level of the TWEAK receptor Fn14 in the HN kidneys, primarily in the distal nephron/collecting duct epithelial cells. In in vitro experiments, kidney epithelial cells did not drive NLRP3 inflammasomes. NLRP3 and ASC alternatively enhanced with-no-lysine (WNK) kinase-mediated NF-κB signaling in response to TWEAK.
Conclusion
Kidney tissue K+ depletion does not engage NLRP3 inflammasome activation, but its components NLRP3 and ASC in kidney epithelia alternatively trigger kidney inflammation by modulating the NF-κB signaling in HN.
Funding
- Government Support – Non-U.S.