Inhibition of Creatine Kinase Activity by Cystine in the Kidney of Young Rats

Abstract

Nephropathic cystinosis is a lethal genetic disease caused by a lysosomal transport disorder leading to intralysosomal cystine accumulation in all tissues. Cystinosis is the most common inherited cause of Fanconi syndrome, but the mechanisms by which cystine causes tissue damage are not fully understood. Thiolcontaining enzymes are critical for renal energy metabolism and may be altered by disulfides like cystine. Therefore, in the present study our main objective was to investigate the in vivo and in vitro effects of cystine on creatine kinase, which contains critical thiol groups in its structure, in the kidney of young Wistar rats. We observed that cystine inhibited in vivo and in vitro the enzyme activity and that this inhibition was prevented by cysteamine and glutathione. The results suggest oxidation of essential sulfhydryl groups necessary for creatine kinase function by cystine. Considering that creatine kinase and other thiol-containing enzymes are crucial for renal energy metabolism, and programmed cell death occurs in situations of energy deficiency, the enzyme inhibition caused by cystine released from lysosomes might be a mechanism of tissue damage in patients with cystinosis. (Pediatr Res 60: 190-195, 2006)

Generation of the oxidized form protects human brain type creatine kinase against cystine-induced inactivation

“…Without treatment, most children with cystinosis develop renal failure, visuospatial difficulties, and increasing discrepancy in a progressive cognitive impairment due to cystine accumulation in the brain [4,5]. Accumulated data indicated that at the molecule level, the high concentration of intracellular cystine affected the activity and functions of many thiol-containing enzymes, such as pyruvate kinase and creatine kinase [6][7][8][9].…”

“…Previous studies have indicated that BBCK is one of the targets of oxidative stresses induced by dis- eases or toxins. Particularly, BBCK inactivation by cystine and cystine dimethyl ester (CDME) has been observed by in vivo studies [6][7][8][9]21,22], while the other CK isoforms seem not to be affected during the pathogenesis of cystinosis [23]. The in vivo studies suggest that cystine or CDME may affect enzyme activity by the induction of free radicals and lipoperoxidation production, the increase of carbonylation of proteins and the decrease of thiol/disulfide ratio [24].…”

Nanocapsules With Naringin And Naringenin Affect Hepatic and Renal Energy Metabolism Without Altering Serum Markers of Toxicity in Rats

“…It catalyzes the reversible transfer of the phosphoryl group from phosphocreatine to ADP, regenerating ATP. For this enzyme there is the mitochondrial isoform (mitCK), which uses ATP to form phosphocreatine and ADP, and the cytosolic isoform (cytCK) that forms creatine through phosphocreatine, generating ATP (Ferreira, 2014;Rech et al 2006Rech et al , 2018. Mg 2+ -ATPase is localized in the plasma membrane of renal and hepatic cells and is essential because it carries the Mg 2+ that is the cofactor of several enzymes involved in energy metabolism (Nozadze et al 2015).…”