Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS

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.

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

“…These findings from human kidneys are preliminary, and additional work is needed before such long-reaching extrapolations can be made. It is curious, however, that podocyte-specific Atg5 deletion 8 did not result in the classic FSGS phenotype that is reported in the work by Kawakami et al 17 Although this could conceivably be explained by incomplete penetrance of podocyte-specific Atg5 deletion in the study by Hartleben et al, 8 the possibility that a coexisting tubule-based autophagy defect is also necessary to produce the full-blown picture must be investigated. How tubule defects might synergize with podocytopathy to produce the FSGS syndrome is something on which to speculate.…”

“…Hartleben et al 8 used podocyte-specific deletion of Atg5 and other interventions to show that podocyte integrity depends on intact autophagic flux; mice with autophagy deficiency in podocytes developed enhanced glomerulosclerosis as they aged (by 20-24 months). Although classic FSGS was not produced, these studies strongly supported autophagic failure as a possible cause for podocytopathy and glomerulosclerosis.A definitive study linking autophagy failure to FSGS is now reported by Kawakami et al 17 Kawakami et al 17 used Six2 promoter-driven Cre expression to delete Atg5 or -7 from all epithelium derived from metanephric mesenchyme. Atg5 deletion from tubules as well as podocytes produced a disease phenotype with uncanny resemblance to human FSGS by 2-4 months and advanced renal failure by 6 months.…”

“…A definitive study linking autophagy failure to FSGS is now reported by Kawakami et al 17 Kawakami et al 17 used Six2 promoter-driven Cre expression to delete Atg5 or -7 from all epithelium derived from metanephric mesenchyme. Atg5 deletion from tubules as well as podocytes produced a disease phenotype with uncanny resemblance to human FSGS by 2-4 months and advanced renal failure by 6 months.…”

“…Buttressing this line of thinking, kidneys also showed a deficiency of Mn-SOD, a superoxide scavenger. Kawakami et al 17 propose that tubule abnormalities and podocytopathy have shared roles to produce the FSGS disease phenotype. In support, Kawakami et al 17 offer electron microscopic evidence for mitochondrial abnormalities in biopsies from patients with FSGS.…”

“…Kawakami et al 17 propose that tubule abnormalities and podocytopathy have shared roles to produce the FSGS disease phenotype. In support, Kawakami et al 17 offer electron microscopic evidence for mitochondrial abnormalities in biopsies from patients with FSGS. These findings from human kidneys are preliminary, and additional work is needed before such long-reaching extrapolations can be made.…”