Lysosomal Cystine Storage Augments Apoptosis in Cultured Human Fibroblasts and Renal Tubular Epithelial Cells

Park, Margaret; Helip-Wooley, Amanda; Thoene, Jess G.

doi:10.1097/01.asn.0000036867.49866.59

Cited by 143 publications

(80 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…40,42,46 Apoptosis is thought to involve the activation of caspases as well as a stereotyped pattern of mitochondrial alterations, namely release of cytochrome c and mitochondrial membrane potential dissipation that contribute to the acquisition of the apoptotic morphology. Apoptosis rate determined by caspases-3 activity in cystinotic RPTE cells has been reported to be significantly increased both with and without an apoptosis trigger.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Autophagy Promotes Cellular Injury in Nephropathic Cystinosis

Sansanwal¹,

Yen

Gahl

et al. 2010

Journal of the American Society of Nephrology

127

113

View full text Add to dashboard Cite

The molecular and cellular mechanisms underlying nephropathic cystinosis, which exhibits generalized proximal tubular dysfunction and progressive renal failure, remain largely unknown. Renal biopsies from patients with this disorder can reveal abnormally large mitochondria, but the relevance of this and other ultrastructural abnormalities is unclear. We studied the ultrastructure of fibroblasts and renal proximal tubular epithelial cells from patients with three clinical variants of cystinosis: Nephropathic, intermediate, and ocular. Electron microscopy revealed the presence of morphologically abnormal mitochondria and abnormal patterns of mitochondrial autophagy (mitophagy) with a high number of autophagic vacuoles and fewer mitochondria (P Ͻ 0.02) in nephropathic cystinosis. In addition, we observed increased apoptosis in renal proximal tubular epithelial cells, greater expression of LC3-II/LC3-I (microtubule-associated protein 1 light chain 3), and significantly more autophagosomes in the nephropathic variant. The autophagy inhibitor 3-methyl adenine rescued cell death in cystinotic cells. Cystinotic cells had increased levels of beclin-1 and aberrant mitochondrial function with a significant decrease in ATP generation and an increase in reactive oxygen species. This study provides ultrastructural and functional evidence of abnormal mitophagy in nephropathic cystinosis, which may contribute to the renal Fanconi syndrome and progressive renal injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Mitochondrial Autophagy Promotes Cellular Injury in Nephropathic Cystinosis

Sansanwal¹,

Yen

Gahl

et al. 2010

Journal of the American Society of Nephrology

127

113

View full text Add to dashboard Cite

show abstract

“…The destruction of individual parenchymal cells, perhaps through enhanced activation of apoptotic mechanisms (29), is considered the basis for tissue injury in nephropathic cystinosis. This process affects the kidney very early; the thyroid gland in late childhood; and the pancreas, muscle, and central nervous system in early adulthood (1,2).…”

Section: Discussionmentioning

confidence: 99%

Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation

Ueda¹,

O’Brien²,

Rosing³

et al. 2006

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Cystinosis, an autosomal recessive disorder of lysosomal cystine accumulation, results from mutations in the CTNS gene that encodes the lysosomal cystine transporter, cystinosin. Renal tubular Fanconi syndrome occurs in infancy, followed by rickets, growth retardation, photophobia, and renal failure, which requires renal transplantation at approximately 10 yr of age. Treatment with cysteamine decreases cellular cystine levels, retards renal deterioration, and allows for normal growth. Patients with a history of inadequate cystine depletion therapy may survive, after renal transplantation, into the third to fifth decades but will experience other, extrarenal complications of the disease. Routine chest and head computed tomography scans of 41 posttransplantation patients with cystinosis were reviewed for vascular calcification. The radiologic procedures had been performed to examine lung and brain parenchyma, so there was little ascertainment bias. Thirteen of the 41 patients had vascular calcification, including 11 with coronary artery calcification. One 25-yr-old man required three-vessel coronary artery bypass graft surgery. There were no significant differences between the 13 patients with calcification and the 28 without calcification in the following parameters: Time on dialysis, frequency of transplantation, hypertension, hypercholesterolemia, homozygosity for the 57-kb deletion in CTNS, serum creatinine, and calcium-phosphate product. However, the finding of vascular calcification correlated directly with duration of life without cysteamine therapy and inversely with duration of life under good cystine-depleting therapy. The accumulation of intracellular cystine itself maybe a risk factor for vascular calcifications, and older patients with cystinosis should be screened for this complication.

show abstract

“…We finally addressed whether, as reported in cultured cells, 33 cystinosis triggered PTC apoptosis, a possible mechanism for crystal clearance, and if apoptotic loss could be corrected by epithelial proliferation. Apoptosis, monitored by activated caspase-3 immunofluorescence, was hardly detected in control kidneys but easy to find in Ctns 2/2 PTCs after 6 months ( Figure 9A, a and b).…”

Section: Ptc Injury Triggers Apoptosis and Epithelial Proliferationmentioning

confidence: 99%

Time Course of Pathogenic and Adaptation Mechanisms in Cystinotic Mouse Kidneys

Chevronnay

Janssens

Smissen

et al. 2014

Journal of the American Society of Nephrology

126

View full text Add to dashboard Cite

Cystinosis, a main cause of Fanconi syndrome, is reproduced in congenic C57BL/6 cystinosin knockout (KO) mice. To identify the sequence of pathogenic and adaptation mechanisms of nephropathic cystinosis, we defined the onset of Fanconi syndrome in KO mice between 3 and 6 months of age and analyzed the correlation with structural and functional changes in proximal tubular cells (PTCs), with focus on endocytosis of ultrafiltrated disulfide-rich proteins as a key source of cystine. Despite considerable variation between mice at the same age, typical event sequences were delineated. At the cellular level, amorphous lysosomal inclusions preceded cystine crystals and eventual atrophy without crystals. At the nephron level, lesions started at the glomerulotubular junction and then extended distally. In situ hybridization and immunofluorescence revealed progressive loss of expression of megalin, cubilin, sodiumglucose cotransporter 2, and type IIa sodium-dependent phosphate cotransporter, suggesting apical dedifferentiation accounting for Fanconi syndrome before atrophy. Injection of labeled proteins revealed that defective endocytosis in S1 PTCs led to partial compensatory uptake by S3 PTCs, suggesting displacement of endocytic load and injury by disulfide-rich cargo. Increased PTC apoptosis allowed luminal shedding of cystine crystals and was partially compensated for by tubular proliferation. We conclude that lysosomal storage triggered by soluble cystine accumulation induces apical PTC dedifferentiation, which causes transfer of the harmful load of disulfide-rich proteins to more distal cells, possibly explaining longitudinal progression of swan-neck lesions. Furthermore, our results suggest that subsequent adaptation mechanisms include lysosomal clearance of free and crystalline cystine into urine and ongoing tissue repair.

show abstract

Lysosomal Cystine Storage Augments Apoptosis in Cultured Human Fibroblasts and Renal Tubular Epithelial Cells

Cited by 143 publications

References 39 publications

Mitochondrial Autophagy Promotes Cellular Injury in Nephropathic Cystinosis

Mitochondrial Autophagy Promotes Cellular Injury in Nephropathic Cystinosis

Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation

Time Course of Pathogenic and Adaptation Mechanisms in Cystinotic Mouse Kidneys

Contact Info

Product

Resources

About