Molecular Mechanisms of Rhabdomyolysis-Induced Kidney Injury: From Bench to Bedside

Hebert, Jessica; Burfeind, Kevin G.; Malinoski, Darren; Hutchens, Michael P.

doi:10.1016/j.ekir.2022.09.026

Cited by 25 publications

(21 citation statements)

References 136 publications

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“…In this respect, it is notable that circulating cell-free hemoglobin (CFH) in patients with sepsis can induce heme-dependent PTEC injury and exacerbate AKI in mouse models of SA-AKI (76,77). Since heme injury to PTECs is also the dominant mechanism of injury in Rhabdo-AKI (78,79), increased reabsorption of CFH and myoglobin from the tubular filtrate in by Megalin-mediated uptake in S1 and S2 PTEC segments that are found throughout the renal cortex (80)(81)(82)(83); this may explain the more widespread activation of RAR signaling in SA-and Rhabdo-AKI compared with IRI-AKI, where PTEC injury and RAR activation is more restricted to PTECs in the OSOM (14).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Yang,

Lopez,

Brewer

et al. 2023

JCI Insight

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PTECs that have phagocytosed apoptotic cells (27). However, in other settings, overexpression of Kim1 may provoke inflammation and fibrosis. For example, a conditional mouse mutant that induces persistent Kim1 expression in renal epithelium provokes renal inflammation and fibrosis in adult mice (30). In addition, persistent Kim1 expression is a feature of inflammatory PTECs that have failed to undergo productive repair after AKI (10,31,32). On this basis, it is unclear whether enhancing Kim1 expression after AKI would be protective or would cause more severe injury and CKD.The retinoic acid (RA) signaling plays an essential role in mammalian kidney development ( 33), but in the adult kidney, RA signaling is restricted to occasional cells within the collecting duct (CD) system (34). RA metabolites are generated in a 2-step process that includes the rate-limiting oxidation of retinaldehyde to RA by retinaldehyde dehydrogenases (RALDHs, encoded by the ALDH1A gene family). Once generated, RAs may act in an autocrine or paracrine fashion and mediate effects by binding to the RA receptors (RARs), which activate or repress transcriptional targets to regulate diverse cellular functions. These effects are cell type and context dependent. For example, RA can promote epithelial differentiation in some circumstances, while in others, it enhances stem cell-like properties (35-37), and RAR signaling promotes heart, limb, and fin appendage regeneration in amphibia and fish (38)(39)(40).We have shown that Raldh2 and Raldh3 are induced in peritubular monocyte/macrophages and myofibroblasts after IRI-AKI and have used RAR reporter mice to show that RAR signaling is activated in adjacent renal macrophages and in injured Kim1 + PTECs after IRI-AKI (41). Systemic inhibition of RAR signaling worsens renal injury and increases inflammatory macrophage activation after IRI-AKI, and macrophage-depletion studies show that worsening injury after inhibition of RAR signaling is dependent on macrophages (41). These findings are consistent with the known antiinflammatory effects of RAR signaling in macrophages (42-46) and the protective effects of exogenous retinoids on renal injury in toxin and IRI-AKI models (41,47,48), in which RA treatments reduce both tubular injury and inflammation in the kidney (41, 47). However, these findings do not explain the functional role that activation of RAR signaling in PTECs plays in the cellular responses to injury, nor whether this response to injury is conserved in patients or in other experimental models of AKI.We now show that PTEC RAR signaling is activated in patients with SA-AKI and mice with Rhabdo-AKI, and we show that inhibition of RAR signaling in PTECs protects against Rhabdo-AKI and, to a lesser extent, IRI-AKI. This is associated with increased Kim1-dependent efferocytosis by PTECs. Increased Kim1 expression is not associated with increased tubular injury but is associated with enhanced dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These findings provide the first gain...

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Section: Discussionmentioning

confidence: 99%

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Yang,

Lopez,

Brewer

et al. 2023

JCI Insight

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“…It is notable that circulating cell free hemoglobin (CFH) detected in patients with sepsis can induce heme-dependent PTEC injury and exacerbate AKI mouse models of SA-AKI (79,80). Since heme injury to PTECs is also the dominant mechanism of injury in rhabdo-AKI (81,82), it is possible that CFH and myoglobin, both of which are reabsorbed from the glomerular filtrate in the proximal S1 and S2 PTEC segments in the renal cortex (83)(84)(85)(86), explains the more widespread activation of RAR signaling in SA-and rhabdo-AKI compared to IRI-AKI, where PTEC injury and RAR activation is more restricted to S3 segment PTECs in the OSOM (14).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Retinoic Acid Signaling in Proximal Tubular Epithelial cells Protects against Acute Kidney Injury by Enhancing Kim-1-dependent Efferocytosis

Yang,

Lopez,

Brewer

et al. 2023

Preprint

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Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development, but in the adult kidney is restricted to occasional collecting duct epithelial cells. We now show there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI), and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protects against experimental AKI but is associated with increased expression of the PTEC injury marker, Kim-1. However, Kim-1 is also expressed by de-differentiated, proliferating PTECs, and protects against injury by increasing apoptotic cell clearance, or efferocytosis. We show that the protective effect of inhibiting PTEC RAR signaling is mediated by increased Kim-1 dependent efferocytosis, and that this is associated with de-differentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate a novel functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.

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“…We read with interest the article titled ‘Molecular mechanisms of rhabdomyolysis-induced kidney injury: from bench to bedside’ by Hebert JF et al. 1 published in Kidney Int Rep . The authors have in detail described a variety of etiologies and the mechanisms of rhabdomyolysis-induced acute tubular injury.…”

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confidence: 99%

“…The authors have in detail described a variety of etiologies and the mechanisms of rhabdomyolysis-induced acute tubular injury. 1 We would like to highlight that snake venom is also an important cause for rhabdomyolysis. 2 Certain bacterial, viral, fungal, and protozoal infections can also lead to rhabdomyolysis.…”

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confidence: 99%

Interesting Histology in Tropical Acute Kidney Injury

Govindan¹,

Fernando²,

Kurien³

2023

Kidney International Reports

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Molecular Mechanisms of Rhabdomyolysis-Induced Kidney Injury: From Bench to Bedside

Cited by 25 publications

References 136 publications

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Inhibition of Retinoic Acid Signaling in Proximal Tubular Epithelial cells Protects against Acute Kidney Injury by Enhancing Kim-1-dependent Efferocytosis

Interesting Histology in Tropical Acute Kidney Injury

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