RESUMEN
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. One of the key mechanisms implicated in the pathogenesis of DN is non-enzymatic glycation (NEG). NEG is the irreversible attachment of reducing sugars onto free amino groups of proteins by a series of events, which include the formation of Schiff's base and an Amadori product to yield advanced glycation end products (AGEs). AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. AGEs activate several intracellular signaling cascades upon interaction with receptor for AGEs (RAGE), which manifest in aberrant cellular responses such as inflammation, apoptosis and autophagy, whereas other receptors such as AGE-R1, AGE-R3 and scavenger receptors also bind to AGEs and ensue endocytosis and degradation of AGEs. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. Increased evidence supports that attenuation of AGE formation and/or inhibition of RAGE activation manifest(s) in improving renal function. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Therapies designed to target AGEs, such as inhibitors of AGEs formation and crosslink breakers, are discussed.
Asunto(s)
Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Transición Epitelial-Mesenquimal , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida , Podocitos/metabolismo , Podocitos/patología , Unión Proteica , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Sistema Renina-AngiotensinaRESUMEN
Cataract, loss of eye lens transparency, is the leading cause of blindness worldwide. alpha-Crystallin, initially known as one of the major structural proteins of the eye lens, is composed of two homologous subunits alphaA- and alphaB-crystallins. It is convincingly established now that alpha-crystallin functions like a chaperone and plays a decisive role in the maintenance of eye lens transparency. The functional ability of alpha-crystallin subunits is to act in cooperation as molecular chaperones to prevent the cellular aggregation and/or inactivation of client proteins under variety of stress conditions. However, chaperone-like activity of alpha-crystallin could be deteriorated or lost during aging or under certain clinical conditions because of various genetic and environmental factors. This review will focus specifically on relevance of alpha-crystallin chaperone function to lens transparency. In particular, we reviewed the studies that demonstrate the modulation of alpha-crystallin chaperone-like activity and discussed the possibility of chaperone-like activity of alpha-crystallin as a potential target to prevent or delay the cataractogenesis.
Asunto(s)
Catarata/metabolismo , Dieta , Cristalino/metabolismo , Chaperonas Moleculares/metabolismo , alfa-Cristalinas/metabolismo , Animales , HumanosRESUMEN
alpha-Crystallin, a molecular chaperone of the eye lens, plays an important role in maintaining the transparency of the lens by preventing the aggregation/inactivation of several proteins and enzymes in addition to its structural role. alpha-Crystallin is a long-lived protein and is susceptible to several posttranslational modifications during aging, more so in certain clinical conditions such as diabetes. Nonenzymatic glycation of lens proteins and decline in the chaperone-like function of alpha-crystallin have been reported in diabetic conditions. Therefore, inhibitors of nonenzymatic protein glycation appear to be a potential target to preserve the chaperone activity of alpha-crystallin and to combat cataract under hyperglycemic conditions. In this study, we investigated the antiglycating potential of cumin in vitro and its ability to modulate the chaperone-like activity of alpha-crystallin vis-à-vis the progression of diabetic cataract in vivo. Aqueous extract of cumin was tested for its antiglycating ability against fructose-induced glycation of goat lens total soluble protein (TSP), alpha-crystallin from goat lens and a nonlenticular protein bovine serum albumin (BSA). The antiglycating potential of cumin was also investigated by feeding streptozotocin (STZ)-induced diabetic rats with diet containing 0.5% cumin powder. The aqueous extract of cumin prevented in vitro glycation of TSP, alpha-crystallin and BSA. Slit lamp examination revealed that supplementation of cumin delayed progression and maturation of STZ-induced cataract in rats. Cumin was effective in preventing glycation of TSP and alpha-crystallin in diabetic lens. Interestingly, feeding of cumin to diabetic rats not only prevented loss of chaperone activity but also attenuated the structural changes of alpha-crystallin in lens. These results indicated that cumin has antiglycating properties that may be attributed to the modulation of chaperone activity of alpha-crystallin, thus delaying cataract in STZ-induced diabetic rats.