The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis

Abstract

Cystinosis is an inherited disorder resulting from a mutation in the CTNS gene, causing progressive proximal tubular cell flattening, the so-called swan-neck lesion (SNL), and eventual renal failure. To determine the role of oxidative stress in cystinosis, histologic sections of kidneys from C57BL/6 Ctns(-/-) and wild-type mice were examined by immunohistochemistry and morphometry from 1 wk to 20 mo of age. Additional mice were treated from 1 to 6 mo with vehicle or mitoquinone (MitoQ), an antioxidant targeted to mitochondria. The leading edge of the SNL lost mitochondria and superoxide production, and became surrounded by a thickened tubular basement membrane. Progression of the SNL as determined by staining with lectin from Lotus tetragonolobus accelerated after 3 mo, but was delayed by treatment with MitoQ (38 ± 4% vs. 28 ± 1%, P < 0.01). Through 9 mo, glomeruli had retained renin staining and intact macula densa, whereas SNL expressed transgelin, an actin-binding protein, but neither kidney injury molecule-1 (KIM-1) nor cell death was observed. After 9 mo, clusters of proximal tubules exhibited localized oxidative stress (4-hydroxynonenal binding), expressed KIM-1, and underwent apoptosis, leading to the formation of atubular glomeruli and accumulation of interstitial collagen. We conclude that nephron integrity is initially maintained in the Ctns(-/-) mouse by adaptive flattening of cells of the SNL through loss of mitochondria, upregulation of transgelin, and thickened basement membrane. This adaptation ultimately fails in adulthood, with proximal tubular disruption, formation of atubular glomeruli, and renal failure. Antioxidant treatment targeted to mitochondria delays initiation of the SNL, and may provide therapeutic benefit in children with cystinosis.

The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives

“…In vivo , the characteristic ‘swan neck’ deformity of the proximal tubules is associated with local apoptosis 104 (FIG. 4).…”

“…In Ctns -knockout mice, the increase in oxidative stress preceded the development of swan neck deformities, which could be delayed by administration of mitoquinone, an antioxidant compound that targets mitochondria 104 . Of interest, a pilot clinical trial in which N -acetyl-cysteine was administered for 3 months to 23 patients with nephropathic cystinosis demonstrated a significant reduction in oxidative stress and improved renal function 114 .…”

“…Interventions that improve any step in these cascades might therefore alleviate the renal Fanconi syndrome. For example, preclinical and a limited clinical study of cysteine supplements or antioxidants indicated favourable outcomes 104,114 ; however, larger studies with longer follow up are needed. Improved understanding of cellular dysfunctions induced by the absence of cystinosin has already identified other potential therapeutic targets.…”

The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

“…); and cystinosis (Galarreta et al. ). Due to the promising protective effects in preclinical studies, MitoQ is now being trialed in humans (Smith and Murphy ).…”

A population of mitochondrion-rich cells in the pars recta of mouse kidney

“…Notably absent from this list are two closely-allied proteins, α-SMA and transgelin, which we have found in kidney epithelium undergoing rapid shape changes, including the glomerulotubular atrophy and scission that occurs in UUO (Forbes et al, 2011) and formation of the cystinotic swan-neck lesions, in which the proximal tubular epithelial cells become severely flattened (Galarreta et al, 2015). The absence of transgelin and α-SMA in mitochondrion-rich S3 tubule cells is confirmed by ultrastructural examination, which found a lack of cytoplasmic filaments.…”