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Project

Collecting duct water reabsorption in cystinosis

Cystinosis is a rare autosomal recessive disease, representing the most common hereditary cause of renal Fanconi syndrome in children, often causing chronic kidney disease (Elmonem et al. Orphanet Journal of Rare Diseases, 2016) (Luciani et al., Autophagy, 2018). The incidence is estimated as 1 in 100,000 –200,000 live births (Wilmer et al., American Journal of Physiology - Renal Physiology, 2010). Cystinosis is a lysosomal storage disease caused by mutations in CTNS gene, encoding for cystinosin, a lysosomal seven-transmembrane protein that transports cystine out of the lysosome (Elmonem et al. 2016). It is a systemic disorder characterized by the abnormal accumulation of the amino acid cystine, leading to intracellular crystals formation throughout the body, which profoundly disturbs cellular oxidative metabolism leading to altered autophagy and enhanced apoptosis (Luciani et al., Autophagy, 2018) (Elmonem et al., Orphanet Journal of Rare Diseases, 2016). The renal phenotype occurs by the age of 6-12 months, affecting initially the proximal tubule and later glomerulus, eventually leading to end-stage renal failure (Elmonem et al., Orphanet Journal of Rare Diseases, 2016). Moreover infants manifest polyuria, polydipsia, episodes of severe dehydration and hypernatremia, consistent with a secondary nephrogenic diabetes insipidus (NDI) phenotype, leading to brain damage and developmental delay (Bockenhauer et al., Nephron - Physiology 2010). Other extra-renal symptoms involve eyes, thyroid, pancreas, gonads, muscles and CNS (Elmonem et al. Orphanet Journal of Rare Diseases, 2016) (Wilmer et al., American Journal of Physiology - Renal Physiology, 2010). Currently, the aminothiol cysteamine is the only target-specific treatment for Cystinosis, however it has no effect on Renal Fanconi Syndrome, making dialysis and kidney transplantion necessary (Elmonem et al. Orphanet Journal of Rare Diseases, 2016). The proposed project aims to investigate the molecular basis of water reabsorption in collecting duct of Cystinosis patients as the secondary NDI phenotype manifested by these patients reflects a possible impairment of this process. Specifically, we will investigate the Vasopressin-aquaporin2 pathway as it plays an essential role in regulating water balance. After Vasopressin is secreted in response to an increase in serum osmolality or a decrease in blood volume, it binds to its receptor, the Vasopressin-2 receptor (V2R), leading to water reabsorption by regulating the Aquaporin-2 water channel (Ranieri et al., F1000Research, 2019). The state of activation of the Vasopressin-AQP2 pathway seems to play a central role in several water balance disorder (Ranieri et al., F1000Research, 2019). In particular, the unresponsiveness of the kidney to the vasopressin stimulus leads to polyuria, polydipsia and risk of severe dehydration due to the inability of the organ to concentrate the urine (Ranieri et al., F1000Research, 2019).

Date:22 Sep 2021 →  Today
Keywords:CYSTINOSIS, NDI
Disciplines:Molecular physiology, Cell physiology
Project type:PhD project