Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

Correia, Maria João; Pimpão, António B.; Fernandes, Dalila G F; Morelló, Judit; Sequeira, Catarina O.; Calado, Joaquim; Antunes, Alexandra M. M.; Almeida, Manuel; Branco, Patrícia; Monteiro, Emília C.; Vicente, João B.; Serpa, Jacinta; Pereira, Sofia A.

doi:10.3390/molecules27041416

Cited by 18 publications

(15 citation statements)

References 231 publications

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“…Disruption of the intracellular thiol antioxidant network progresses to non-apoptotic, iron-dependent, oxidative cell death, termed ferroptosis ( 9 ). In many cells, GSH synthesis is dependent on the continuous import of cysteine by the cell surface Cys 2 /glutamate antiporter system x c - ( 63 , 64 ), the heterodimer of a membrane protein b 0,+ AT/SLC7A9, and its auxiliary subunit rBAT/SLC3A1, which is responsible for cysteine reabsorption, particularly in renal proximal tubules ( 65 – 68 ). Although Slc7a9 mutations have been reported to cause cystinuria, their functions in protecting proximal tubular cells against iron-induced oxidative damage ( 65 , 66 , 68 ) and ferroptosis are unclear.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis

et al. 2023

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BackgroundApproximately 30% of diabetic patients develop diabetic nephropathy, a representative microvascular complication. Although the etiological mechanism has not yet been fully elucidated, renal tubular damage by hyperglycemia-induced expression of transforming growth factor-β (TGF-β) is known to be involved. Recently, a new type of cell death by iron metabolism called ferroptosis was reported to be involved in kidney damage in animal models of diabetic nephropathy, which could be induced by TGF-β. Bone morphogenetic protein-7 (BMP7) is a well-known antagonist of TGF-β inhibiting TGF-β-induced fibrosis in many organs. Further, BMP7 has been reported to play a role in the regeneration of pancreatic beta cells in diabetic animal models.MethodsWe used protein transduction domain (PTD)-fused BMP7 in micelles (mPTD-BMP7) for long-lasting in vivo effects and effective in vitro transduction and secretion.ResultsmPTD-BMP7 successfully accelerated the regeneration of diabetic pancreas and impeded progression to diabetic nephropathy. With the administration of mPTD-BMP7, clinical parameters and representative markers of pancreatic damage were alleviated in a mouse model of streptozotocin-induced diabetes. It not only inhibited the downstream genes of TGF-β but also attenuated ferroptosis in the kidney of the diabetic mouse and TGF-β-stimulated rat kidney tubular cells.ConclusionBMP7 impedes the progression of diabetic nephropathy by inhibiting the canonical TGF-β pathway, attenuating ferroptosis, and helping regenerate diabetic pancreas.

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis

et al. 2023

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“…J Physiol 601.24 2008). Glutathione availability and protein S-thiolation contribute to vascular homeostasis (Lermant & Murdoch, 2019) and indicate the extent of oxidative stress (Correia et al, 2022;Fu et al, 2019). However, using the same paradigm, after 3 weeks of CIH (with established HTN) an upregulation of expression markers for expression RAAS (renin, AT1 receptor, but not Ace 1), ER stress (Gpr78) and inflammation (RelA, but not Il1b, Il6, p49/p100) was observed in the kidney (Coelho et al, 2020).…”

Section: Figure 3 Schematic Representation Of the Deleterious Effects...mentioning

confidence: 98%

“…In this model, short‐term CIH (up to 7 days), wherein no or mild changes in BP were observed (Diogo, Pereira et al., 2015), increased total glutathione availability (Correia et al., 2021) and protein S ‐thiolation, a post‐translational modification that might protect proteins from irreversible oxidation (Dalle‐Donne et al., 2008). Glutathione availability and protein S ‐thiolation contribute to vascular homeostasis (Lermant & Murdoch, 2019) and indicate the extent of oxidative stress (Correia et al., 2022; Fu et al., 2019). However, using the same paradigm, after 3 weeks of CIH (with established HTN) an upregulation of expression markers for expression RAAS (renin, AT1 receptor, but not Ace 1), ER stress ( Gpr 78) and inflammation ( RelA , but not Il1b , Il6 , p49/p100 ) was observed in the kidney (Coelho et al., 2020).…”

Section: Introduction: Sleep Apnoea Chronic Intermittent Hypoxia and ...mentioning

confidence: 99%

“…However, using the same paradigm, after 3 weeks of CIH (with established HTN) an upregulation of expression markers for expression RAAS (renin, AT1 receptor, but not Ace 1), ER stress ( Gpr 78) and inflammation ( RelA , but not Il1b , Il6 , p49/p100 ) was observed in the kidney (Coelho et al., 2020). Moreover, CIH exposure (35–60 days of exposure to the same paradigm) increased cysteine disulfides, which are non‐radical oxidative and inflammatory molecules (Correia et al., 2022) and by 8–9 weeks of exposure a decrease in glutathione availability was observed (Correia et al., 2021).…”

Section: Introduction: Sleep Apnoea Chronic Intermittent Hypoxia and ...mentioning

confidence: 99%

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Chronic intermittent hypoxia‐induced cardiovascular and renal dysfunction: from adaptation to maladaptation

Arnaud,

Billoir,

de Melo Junior

et al. 2023

The Journal of Physiology

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Chronic intermittent hypoxia (CIH) is the dominant pathological feature of human obstructive sleep apnoea (OSA), which is highly prevalent and associated with cardiovascular and renal diseases. CIH causes hypertension, centred on sympathetic nervous overactivity, which persists following removal of the CIH stimulus. Molecular mechanisms contributing to CIH‐induced hypertension have been carefully delineated. However, there is a dearth of knowledge on the efficacy of interventions to ameliorate high blood pressure in established disease. CIH causes endothelial dysfunction, aberrant structural remodelling of vessels and accelerates atherosclerotic processes. Pro‐inflammatory and pro‐oxidant pathways converge on disrupted nitric oxide signalling driving vascular dysfunction. In addition, CIH has adverse effects on the myocardium, manifesting atrial fibrillation, and cardiac remodelling progressing to contractile dysfunction. Sympatho‐vagal imbalance, oxidative stress, inflammation, dysregulated HIF‐1α transcriptional responses and resultant pro‐apoptotic ER stress, calcium dysregulation, and mitochondrial dysfunction conspire to drive myocardial injury and failure. CIH elaborates direct and indirect effects in the kidney that initially contribute to the development of hypertension and later to chronic kidney disease. CIH‐induced morphological damage of the kidney is dependent on TLR4/NF‐κB/NLRP3/caspase‐1 inflammasome activation and associated pyroptosis. Emerging potential therapies related to the gut–kidney axis and blockade of aryl hydrocarbon receptors (AhR) are promising. Cardiorenal outcomes in response to intermittent hypoxia present along a continuum from adaptation to maladaptation and are dependent on the intensity and duration of exposure to intermittent hypoxia. This heterogeneity of OSA is relevant to therapeutic treatment options and we argue the need for better stratification of OSA phenotypes. image

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“…The levels of the free radicals and reactive species are reduced by the glutathione directly or enzymatically [ 25 ]. The presence of the reactive oxidative agents can be lowered by the cysteine that is present in the cells in the bonded or non-bonded forms [ 26 ]. The onset of the hyperglycemia also influences the expressions and activity of P-gp, MRP-2, BCRP and the activity of various metabolic enzymes (uridine glucuronyltransferase and sulfotransferase) in the metabolizing organs [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Investigation of Intestinal Absorption and Excretion of Paracetamol in Streptozotocin-Induced Hyperglycemia

Mészáros

Kovács

Kulcsár

et al. 2022

IJMS

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The phenolic drug molecules can be metabolized, among others, by the small intestine’s enterocytes. The conjugation reactions (glucuronidation and sulfation) show great importance in these transformations, although the oxidation reactions can be significant. These processes are dependent on the substituents of the phenolic compounds or the reacting functional groups (hydroxyl or carboxyl). Pathologic conditions, e.g., permanent hyperglycemia and diabetes, can alter the activities of the conjugative and possibly the oxidative enzymes, thus forming a change in the metabolic pattern and eventually provoking oxidative stress. A rat intestinal perfusion model was used to investigate the way in which experimental hyperglycemia affects the paracetamol’s intestinal elimination and metabolism. Hyperglycemia was induced by the administration of streptozotocin. Two hundred and fifty µM paracetamol was used in the intestinal perfusion solution. For the quantitation of the paracetamol and its major metabolites in the intestinal perfusate, an isocratic high-performance liquid chromatography method with UV-Vis detection was developed. The results revealed that quantities of all of the measured metabolites (glucuronide, sulfate, cysteine, and mercapturic acid conjugates) increased as the effect of the streptozotocin-induced hyperglycemia also did. In the small intestine’s homogenate, the glutathione levels showed that there was a decrease in the hyperglycemia levels after the paracetamol administration. In contrast, the tissue levels of the cysteine were lower in the streptozotocin-induced hyperglycemia and increased after the administration of the paracetamol. The changes in the activity of the intestinal CYP 3A4, CYP 2E1, and cyclooxygenase (COX) enzymes were determined in the control and the hyperglycemic cases. Still, there was a significant observable enzyme activity elevation in the intestinal COX enzymes, but there was a decrease in the amount of activity of the intestinal CYP3A4 enzymes, and the CYP2E1 enzyme activity was practically changeless. The results on the cysteine levels in the intestinal homogenate, at least partly, can be explained by the regulation function of the cysteine during the occurrence of oxidative stress.

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Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

Cited by 18 publications

References 231 publications

Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis

Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis

Chronic intermittent hypoxia‐induced cardiovascular and renal dysfunction: from adaptation to maladaptation

Investigation of Intestinal Absorption and Excretion of Paracetamol in Streptozotocin-Induced Hyperglycemia

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