Could Autophagic Exhaustion Be a Final Common Pathway for Podocytopathy in FSGS?

Abstract

Among renal syndromes caused by glomerular disorders, FSGS continues to pose the most challenges in understanding its pathogenesis and therefore, in arriving at mechanism-based approaches for its treatment. The extraordinary diversity of genetic etiologies linked to primary FSGS, the sizable number of patients with idiopathic disease, and the disparate clinical conditions unrelated to primary FSGS that manifest the pathology of secondary FSGS make it difficult to formulate a unifying theory of pathogenesis. 1,2 The common feature that links together diverse genetically determined FSGS, idiopathic FSGS, and other toxic, infective, metabolic, and hemodynamic disorders that cause secondary FSGS is, of course, segmental and global scarring of glomeruli, a pathology now linked to development of podocytopathy. 1,2 Pathologic features can vary among the gamut of primary and secondary FSGS, but research points to the podocyte as the seat of early as well as continuing responsible pathology. According to evolving dogma, decrease in absolute podocyte numbers primarily, such as in oligomeganephronia, secondarily, through nephron loss by disease, or by cell death during disease is a major factor that fosters progressive glomerular damage. In this line of reasoning, podocytes decrease in number either relatively with respect to the demands of glomerular hypertrophy-such as in remnant kidneys after nephron loss by disease-or by cell death through disease-associated podocytopathy. As a result, remaining podocytes cannot adequately cover the outer surfaces of glomerular capillaries with the differentiated protoplasm required for structural integrity and barrier function. 3,4 In large part, this is caused by the inability of terminally differentiated podocytes to replenish the population through cell division. 4 Being possessed of unique structural and biologic attributes that make them vulnerable, surviving podocytes seem unable to adapt and withstand the hemodynamic, metabolic, aging, or disease-related stresses imposed on them or the stresses of pathologic signaling, oxidant injury, misfolded protein responses, cytoskeletal perturbations, or intracellular proteolysis-abnormalities caused by specific genetic mutations or other disease. If extreme, such stresses cause podocytopathy, cell death, additional podocyte depletion, and secondary endocapillary and mesangial pathologies characteristic of the sclerotic lesion. This pathology progresses segmentally and globally in autonomous vicious cycles: locally within glomeruli, serially injuring and killing adjacent podocytes, and through systemic effects, recruiting more glomeruli to the sclerotic process. [4][5][6] Because the instigating factors that cause secondary FSGS are so disparate and the genetic abnormalities that underlie primary FSGS are so unrelated to each other-affecting proteins related to slit diaphragms, cation channels, mitochondrial proteins, or cytoskeletal proteins-the question arises: is there a common cellular process that connects them, possibly as a final c...

Perturbations in podocyte transcriptome and biological pathways induced by FSGS associated circulating factors

“…In addition, the involvement of ApoL1 as a non-specific final common pathway for podocytopathy is supported by studies showing that dysregulation in ApoL1 levels can lead to autophagic cell death ( 49 - 51 ). While the role of autophagic cell death in the development of FSGS or other podocytopathies are speculative at this time, there are studies suggesting a connection ( 52 - 54 ). Deletion of the autophagy associated E1-like activating enzyme, autophagy related 5 ( ATG5 ) in podocytes and tubular epithelial cells results in FSGS like phenotype in mice ( 53 ).…”

Glomerular Effects of Age and APOL1

“…In particular, there has been speculation that APOL1 risk alleles cause podocyte injury. 11 We may, thus, expect to see studies examining whether APOL1 risk alleles cause the acceleration of the age-related podocyte loss that was described by Hodgin et al 1 or other podocyte abnormalities. Also, the report of Hoy et al, 3 although it does not show an overall difference in the kidneys of African Americans with and without APOL1 risk alleles, does reveal a potential effect of these alleles on aging.…”

“…8 Autophagy is thought to be particularly important to the long-term survival of terminally differentiated neurons and by analogy, podocytes, which cannot lower their concentration of cytoplasmic debris by division. [8][9][10][11] Reduced autophagy could, thus, cause podocyte loss with aging, even when no additional podocyte stress is imposed by glomerular hypertrophy. If this is the case, we might expect to observe accumulation of dysfunctional mitochondria and other debris in aging podocytes.…”