Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity

Zmijewska, Anna A.; Żmijewski, Jaroslaw W.; Becker, Eugene; Benavides, Gloria A.; Darley‐Usmar, Victor; Mannon, Roslyn B.

doi:10.1111/ajt.16561

Cited by 11 publications

(10 citation statements)

References 56 publications

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“…Stimulated Arl8b expression standing for enhanced lysosomal exocytosis, which we observed in the proximal tubule of the CsA group, supported the lysosomal issue (66). Upregulated HMGB1 and CTSD further suggested bioenergetic maladaption and mitochondrial dysfunction along with enhanced autophagy in CsA (60,67,68). The disorder may have been accompanied by oxidative stress since catalase was selectively stimulated in CsA along with activated proximal tubular peroxisomes, suggesting enhanced scavening of ROS (69).…”

Section: Discussionsupporting

confidence: 59%

“…Tubular damage in CNI nephropathy has been extensively discussed in the past, yet it has remained uncertain whether direct toxicity to epithelia or downstream effects of affected vasculature or glomerular function prevail at its origin. Published data point to the proximal tubule as the principal nephron segment involved in pathogenesis, reporting vacuolization, loss of BBM, bioenergetic maladaptation, atrophy, and fibrotic decay with no major causative distinction between CsA and Tac (59,60). Contrastingly, our data have shown substantial differences in proximal tubular damage.…”

Section: Discussioncontrasting

confidence: 48%

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Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

Demirci

Popović

Dittmayer

et al. 2023

Preprint

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Calcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects notoriously contribute to allograft injury despite attempts to optimize their application, often with additional medications. The etiology of chronic renal parenchymal changes is complex irrespective of chosen therapy with either cyclosporine A (CsA) or currently favoured tacrolimus (Tac). The pathogenetic detail of their respective toxicities has not been fully understood. To test whether CsA and Tac cause adverse renal responses differentially, we employed a chronic rat model with continous drug application. Histopathology of the renal compartments was combined with multiomics analysis. Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction and enhanced apoptosis along with impaired proteostasis and oxidative stress. We conclude that pathogenetic alterations in renal microenvironments are specific for either treatment. We have identified related biomarkers to adequately address chronic CNI nephropathy in transplant recipients.

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Section: Discussionsupporting

confidence: 59%

Section: Discussioncontrasting

confidence: 48%

Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

Demirci

Popović

Dittmayer

et al. 2023

Preprint

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“…For instance, imidacloprid stress induces Nrf2 inactivation and mediates HMGB1/RAGE/TLR4 signaling activation, thereby triggering iron death and leading to the initial wave of death that fuels pyroptosis and exacerbates renal dysfunction [62]. Similarly, cyclosporine, aristolochic acid I, and calcineurin inhibitors also promote HMGB1 secretion by tubular cells, aggravating tubular injury and renal fibrosis [63][64][65], suggesting that HMGB1 might serve as an early indicator and marker of progressive nephrotoxicity. Although neutralization of extracellular HMGB1 is beneficial, intracellular HMGB1 seems to play an additional role in renal tubular injury [51].…”

Section: Hmgb1 and Proximal Tubule Epithelial Cellmentioning

confidence: 99%

Targeting HMGB1: A Potential Therapeutic Strategy for Chronic Kidney Disease

Liu,

Li,

Jin

et al. 2023

Int. J. Biol. Sci.

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High-mobility group protein box 1 (HMGB1) is a member of a highly conserved high-mobility group protein present in all cell types. HMGB1 plays multiple roles both inside and outside the cell, depending on its subcellular localization, context, and post-translational modifications. HMGB1 is also associated with the progression of various diseases. Particularly, HMGB1 plays a critical role in CKD progression and prognosis. HMGB1 participates in multiple key events in CKD progression by activating downstream signals, including renal inflammation, the onset of persistent fibrosis, renal aging, AKI-to-CKD transition, and important cardiovascular complications. More importantly, HMGB1 plays a distinct role in the chronic pathophysiology of kidney disease, which differs from that in acute lesions. This review describes the regulatory role of HMGB1 in renal homeostasis and summarizes how HMGB1 affects CKD progression and prognosis. Finally, some promising therapeutic strategies for the targeted inhibition of HMGB1 in improving CKD are summarized. Although the application of HMGB1 as a therapeutic target in CKD faces some challenges, a more in-depth understanding of the intracellular and extracellular regulatory mechanisms of HMGB1 that underly the occurrence and progression of CKD might render HMGB1 an attractive therapeutic target for CKD.

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“…In this, the bioenergetic reprogramming—with a switch from oxidative phosphorylation to glycolytic metabolism—induced by cyclosporine stands out. 1 , 6 …”

mentioning

confidence: 99%

Modest but impactful: Commentary on immunosuppressive drugs for nontransplant comorbidities are not associated with abdominal aortic aneurysm growth

Lindeman

2022

JVS-Vascular Science

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Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity

Cited by 11 publications

References 56 publications

Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

Targeting HMGB1: A Potential Therapeutic Strategy for Chronic Kidney Disease

Modest but impactful: Commentary on immunosuppressive drugs for nontransplant comorbidities are not associated with abdominal aortic aneurysm growth

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