The proximal tubule in cystinosis: fight or flight?

Although rare, nephropathic cystinosis is a devastating monogenic disorder leading to renal failure in the second decade of life. Fanconi syndrome, the initial renal manifestation of cystinosis in the young child, established the proximal tubule as a primary target of injury now recognized as the result of mutations in cystinosin (CTNS), the lysosomal cystine-proton cotransporter.1 A major challenge in understanding the pathophysiology of cystinosis remains: what is the link between lysosomal cystine accumulation andproximal tubular dysfunction? Most of the data generated to date are based on in vitro studies of proximal tubular cells incubated with cystine dimethyl ester or of cells from cystinotic patients. These have resulted in the formulation of three major hypotheses regarding cystine-induced injury of proximal tubular cells: altered ATPmetabolism, altered glutathionemetabolism, and apoptotic cell death.1 Mitochondria in cystinotic proximal tubules are abnormal, and cells contain decreased ATP and glutathione and undergo increased apoptosis. The interpretation of ATP metabolism in cell culture studies is hampered by the stimulation of glycolytic activity in vitro, whereas ATP is derived from mitochondrial oxidative phosphorylation in vivo.1 Progress has been accelerated by the recent availability of an animal model with a renal phenotype similar to human nephropathic cystinosis. The C56BL/6 Ctnsmouse exhibits most of the features of the human disease, including the formation of the “swan-neck deformity,” a marked progressive narrowing of the proximal tubule beginning at the glomerulotubular junction.2 Two papers in this issue of JASN have elucidated cellular mechanisms underlying the proximal tubular injury in the Ctns mouse. Using a combination of techniques, including light, multiphoton, and electron microscopy, as well as functional endocytosis assays, Chevronnay et al.3 demonstrate the evolution of lysosomal inclusions in proximal tubular cells leading to apical dedifferentiation, characterized by the loss in the S1 segment of expression of megalin, cubulin, and other transporters. This is accompanied by cellular adaptation, including expulsion of cystine crystals and tubular remodeling by downstream proximal tubular segments. Using in vitro studies of human peripheral blood mononuclear cells exposed to cystine crystals, as well as in vivo studies of the Ctns mouse model, Prencipe et al.4 conclude that cystine crystals activate inflammasomes, most likely in proximal tubular cells, resulting in the release of IL-1b and IL-18. This, in turn, may contribute to the interstitial inflammation and fibrosis present in terminal phases of the human and murine Ctns mutants. The relative contribution of crystal-induced inflammasomes to cystinotic tubular injury remains to be determined, however. It is estimated that only 1% of intracellular cystine crystals are retained, due to lysosomal discharge of the crystals linked to endocytic recycling.3 The swan neck, a morphologic hallmark of cystinosis, can be viewed as a degenerative process that leaves a nonfunctional proximal tubular “atrophic” segment.3 However, the development of extremely thin cells lining thickened tubular basement membrane may instead represent an adaptation to mitochondrial injury resulting from defective intracellular cystine processing. The proximal tubules comprise the bulk of renalmass and consume themajority of energy in reabsorption of glomerular filtrate. This tubular segment is particularly susceptible to oxidative injury resulting from a variety of stimuli, ranging from metabolic toxins (cystine accumulation) to ischemic or obstructive processes. Suchoxidative injury is compounded by the generation of reactive oxidant species by damaged mitochondria.5 Compared with the distal nephron, which has robust endogenous antioxidant defenses, the proximal tubule is more vulnerable to oxidative injury.6 Thus, thinning of proximal tubular cells and thickening of tubular basement membrane can be viewed as an adaptive response: the machinery for cystine uptake has been eliminated by the tubular segment first exposed to cystine-rich glomerular filtrate. In this regard, megalin activity has been shown to contribute to early injury of proximal tubular cells in a model of nonselective proteinuria: loss of megalin is protective.7 Moreover, by markedly decreasing mitochondrial content, formation of the swan neck in Ctns mice reduces energy consumption and provides a structurally sound conduit to transport filtrate to functioning tubular cells downstream. This is, of course, only a temporizing measure— the transfer of function by the S1 segment of the proximal tubule to the S3 segment demonstrated by Chevronnay et al.3 eventually fails to maintain nephron function, and proximal tubular cell death ensues, with the eventual formation of atubular glomeruli.8 What begins as an effective short-term adaptation ultimately becomes maladaptive. A useful paradigm to explain adaptations to injurious stimuli was drafted by Goligorsky, who applied Cannon’s Published online ahead of print. Publication date available at www.jasn.org.