Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS
Takahisa Kawakami1, Ivan G Gomez1, Shuyu Ren2
1Division of Nephrology, Departments of Medicine & Pathology, and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan;
Abstract:
FSGS is a heterogeneous fibrosing disease of the kidney, the cause of which remains poorly understood. In most cases, there is no effective treatment to halt or retard progression to renal failure. Increasing evidence points to mitochondrial dysfunction and the generation of reactive oxygen species in the pathogenesis of CKD. Autophagy, a major intracellular lysosomal degradation system, performs homeostatic functions linked to metabolism and organelle turnover. We prevented normal autophagic pathways in nephrons of mice by mutating critical autophagy genes ATG5 or ATG7 during nephrogenesis. Mutant mice developed mild podocyte and tubular dysfunction within 2 months, profound glomerular and tubular changes bearing close similarity to human disease by 4 months, and organ failure by 6 months. Ultrastructurally, podocytes and tubular cells showed vacuolization, abnormal mitochondria, and evidence of endoplasmic reticulum stress, features that precede the appearance of histologic or clinical disease. Similar changes were observed in human idiopathic FSGS kidney biopsy specimens. Biochemical analysis of podocytes and tubules of 2-month-old mutant mice revealed elevated production of reactive oxygen species, activation of endoplasmic reticulum stress pathways, phosphorylation of p38, and mitochondrial dysfunction. Furthermore, cultured proximal tubule cells isolated from mutant mice showed marked mitochondrial dysfunction and elevated mitochondrial reactive oxygen species generation that was suppressed by a mitochondrial superoxide scavenger. We conclude that mitochondrial dysfunction and endoplasmic reticulum stress due to impaired autophagic organelle turnover in podocytes and tubular epithelium are sufficient to cause many of the manifestations of FSGS in mice.
Insights
Impaired autophagy in kidney cells causes mitochondrial dysfunction and ER stress, leading to kidney disease similar to human FSGS. This study reveals a key mechanism in kidney fibrotic disease progression.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Biology
Background:
- Focal Segmental Glomerulosclerosis (FSGS) is a kidney disease with unknown causes and no effective treatments.
- Mitochondrial dysfunction and reactive oxygen species (ROS) are implicated in chronic kidney disease (CKD) pathogenesis.
- Autophagy is a cellular process crucial for maintaining cellular homeostasis and organelle turnover.
Purpose of the Study:
- To investigate the role of autophagy in the pathogenesis of FSGS.
- To determine if impaired autophagy in nephrons can induce FSGS-like kidney disease.
- To explore the link between autophagy, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in FSGS.
Main Methods:
- Generated mutant mice lacking essential autophagy genes (ATG5 or ATG7) in nephrons.
- Analyzed kidney structure and function at various time points (2, 4, and 6 months).
- Performed ultrastructural, biochemical, and cell culture analyses to assess cellular damage and dysfunction.
Main Results:
- Mutant mice developed progressive kidney damage, including podocyte and tubular dysfunction, resembling human FSGS.
- Ultrastructural analysis revealed vacuolization, mitochondrial abnormalities, and ER stress in podocytes and tubular cells.
- Biochemical studies showed elevated ROS production, ER stress activation, and mitochondrial dysfunction in mutant mice kidneys.
- Impaired autophagy led to mitochondrial dysfunction and increased mitochondrial ROS generation in cultured kidney cells.
Conclusions:
- Impaired autophagic organelle turnover in podocytes and tubular epithelium is sufficient to cause FSGS manifestations.
- Mitochondrial dysfunction and ER stress are key consequences of defective autophagy in kidney disease.
- This study highlights a novel mechanism linking autophagy to FSGS pathogenesis, offering potential therapeutic targets.
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