Co-administration of angiotensin II and simvastatin triggers kidney injury upon heme oxygenase-1 deficiency

Kopacz, Aleksandra; Klóska, Damian; Cysewski, Dominik; Kraszewska, Izabela; Przepiórska, Karolina; Lenartowicz, Małgorzata; Łoboda, Agnieszka; Grochot-Przęczek, Anna; Nowak, Witold; Józkowicz, Alicja; Piechota-Polańczyk, Aleksandra

doi:10.1016/j.freeradbiomed.2023.05.018

Cited by 2 publications

(1 citation statement)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a recent work published on August 2023 employing HO-1 knock-out mice, the administration of simvastatin along with angiotensin II provoked renal injury due to accelerated rabdomyolysis [236]. In those animals that survived, the high deposition of heme to kidneys was accompanied by an upregulated metabolism of GSH as an alternative pathway to defend.…”

Section: Gsh-hematin Adducts: Characterization Mechanism Of Formation...mentioning

confidence: 99%

The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates

Georgiou-Siafis,

Tsiftsoglou

2023

Antioxidants

View full text Add to dashboard Cite

Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1–5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS. A generally underestimated mechanism of action of GSH is its direct nucleophilic interaction with electrophilic compounds yielding thioether GSH S-conjugates. Many compounds, including xenobiotics (such as NAPQI, simvastatin, cisplatin, and barbital) and intrinsic compounds (such as menadione, leukotrienes, prostaglandins, and dopamine), form covalent adducts with GSH leading mainly to their detoxification. In the present article, we wish to present the key role and significance of GSH in cellular redox biology. This includes an update on the formation of GSH-S conjugates or GSH adducts with emphasis given to the mechanism of reaction, the dependence on GST (GSH S-transferase), where this conjugation occurs in tissues, and its significance. The uncovering of the GSH adducts’ formation enhances our knowledge of the human metabolome. GSH–hematin adducts were recently shown to have been formed spontaneously in multiples isomers at hemolysates, leading to structural destabilization of the endogenous toxin, hematin (free heme), which is derived from the released hemoglobin. Moreover, hemin (the form of oxidized heme) has been found to act through the Kelch-like ECH associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway as an epigenetic modulator of GSH metabolism. Last but not least, the implications of the genetic defects in GSH metabolism, recorded in hemolytic syndromes, cancer and other pathologies, are presented and discussed under the framework of conceptualizing that GSH S-conjugates could be regarded as signatures of the cellular metabolism in the diseased state.

show abstract

Section: Gsh-hematin Adducts: Characterization Mechanism Of Formation...mentioning

confidence: 99%

The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates

Georgiou-Siafis,

Tsiftsoglou

2023

Antioxidants

View full text Add to dashboard Cite

show abstract

Reduction in Renal Heme Oxygenase-1 Is Associated with an Aggravation of Kidney Injury in Shiga Toxin-Induced Murine Hemolytic-Uremic Syndrome

Mestekemper,

Pirschel,

Krieg

et al. 2024

Toxins

View full text Add to dashboard Cite

Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the relevance of the heme-degrading enzyme heme oxygenase-1 (HO-1, encoded by Hmox1) in HUS has not yet been investigated. We hypothesized that HO-1, also important in acute phase responses in damage and inflammation, contributes to renal pathogenesis in HUS. The effect of tamoxifen-induced Hmox1 gene deletion on renal HO-1 expression, disease progression and AKI was investigated in mice 7 days after HUS induction. Renal HO-1 levels were increased in Stx-challenged mice with tamoxifen-induced Hmox1 gene deletion (Hmox1R26Δ/Δ) and control mice (Hmox1lox/lox). This HO-1 induction was significantly lower (−43%) in Hmox1R26Δ/Δ mice compared to Hmox1lox/lox mice with HUS. Notably, the reduced renal HO-1 expression was associated with an exacerbation of kidney injury in mice with HUS as indicated by a 1.7-fold increase (p = 0.02) in plasma neutrophil gelatinase-associated lipocalin (NGAL) and a 1.3-fold increase (p = 0.06) in plasma urea, while other surrogate parameters for AKI (e.g., periodic acid Schiff staining, kidney injury molecule-1, fibrin deposition) and general disease progression (HUS score, weight loss) remained unchanged. These results indicate a potentially protective role of HO-1 in the pathogenesis of Stx-mediated AKI in HUS.

show abstract

Co-administration of angiotensin II and simvastatin triggers kidney injury upon heme oxygenase-1 deficiency

Cited by 2 publications

References 75 publications

The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates

The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates

Reduction in Renal Heme Oxygenase-1 Is Associated with an Aggravation of Kidney Injury in Shiga Toxin-Induced Murine Hemolytic-Uremic Syndrome

Contact Info

Product

Resources

About