Cystinosis is an inherited disorder resulting from a mutation in CTNS, causing progressive proximal tubular cell flattening, the "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 week to 20 months of age (mo). 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 thickened tubular basement membrane. Progression of the SNL as determined by Lotus tetragonolobus staining accelerated after 3 mo, but was delayed by treatment with MitoQ (38±4% vs. 28±1%, p<0.01). Through 9 mo, glomeruli retained renin staining and intact macula densa while SNL expressed transgelin, an actin-binding protein, but not kidney injury molecule-1 (KIM-1) or cell death (TUNEL). After 9 mo, clusters of proximal tubules localized oxidative stress (4-hydroxynonenal binding), expressed KIM-1, and underwent apoptosis (TUNEL), leading to formation of atubular glomeruli and accumulation of interstitial collagen (picrosirius). We conclude that nephron integrity is initially maintained in the Ctns-/- mouse by adaptive flattening of cells of the SNL, with reduced 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 cystinotic children.
- swan-neck lesion
- oxidative injury
- Copyright © 2014, American Journal of Physiology - Renal Physiology