Abstract: TH-PO0376
GLS1 Deficiency Drives RIPK1-Mediated Podocyte PANoptosis in Diabetic Kidney Disease
Session Information
- Glomerular Diseases: Genetics to Therapeutics
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
- Tao, Yilin, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
- Li, Xuehong, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
- Cheng, Wang, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
Background
Podocyte injury is a major pathological feature of diabetic kidney disease (DKD) and contributes to disease progression. Whether and how dysregulated glutamine metabolism drives podocyte injury remains unclear. Here, we identified GLS1 (glutaminase), a key enzyme in glutamine metabolism, as a clinically relevant mediator of podocyte injury.
Methods
Proteomic analysis was performed on renal tissues from patients with diabetic nephropathy(n=17) and peritumoral controls(n=12), and metabolomic profiling was conducted in db/m and db/db mouse kidneys. GLS1 expression and glutamine/glutamate levels were validated in clinical biopsies, diabetic models, and cultured podocytes. GLS1 function was examined using glutamate supplementation, podocyte-specific GLS1 knock-in mice, and GLS1 knockdown or overexpression in podocytes. The role of GLS1 in podocyte PANoptosis was investigated in vitro and in vivo.
Results
Integrated proteomic and metabolomic analyses revealed reduced glutamate levels and marked GLS1 downregulation in DKD. Podocyte GLS1 expression was significantly decreased in clinical DKD biopsies, and glomerular GLS1 levels negatively correlated with UACR. GLS1 downregulation was confirmed in db/db mice, STZ-induced diabetic mice, and high-glucose-treated human podocytes. In vivo, glutamate supplementation improved podocyte dysfunction in diabetic mice, while podocyte-specific GLS1 knock-in alleviated diabetic podocyte injury. In vitro, GLS1 knockdown aggravated podocyte injury and promoted PANoptosis, whereas GLS1 overexpression attenuated high-glucose-induced injury and PANoptosis. Mechanistically, RIPK1 knockdown rescued GLS1 deficiency-induced PANoptosis, indicating that GLS1 loss promotes podocyte PANoptosis through RIPK1 activation. α-Ketoglutarate (α-KG) supplementation also attenuated GLS1 knockdown-induced PANoptosis.
Conclusion
GLS1 deficiency is clinically associated with DKD severity and drives podocyte injury through RIPK1-mediated PANoptosis. Restoring GLS1-mediated glutamate production may represent a promising strategy to protect podocytes and ameliorate DKD progression.
Funding
- Government Support – Non-U.S.