How Kidney Cell Death Induces Renal Necroinflammation

Mulay, Shrikant R.; Kumar, Santhosh V.; Lech, Maciej; Desai, Jyaysi; Anders, Hans‐Joachim

doi:10.1016/j.semnephrol.2016.03.004

Cited by 45 publications

(27 citation statements)

References 141 publications

(173 reference statements)

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“…Necroinflammation is the central pathomechanism of ischaemic and toxic AKI [11,24,25,32,34,35,52]. The induction of RIPK3, MLKL and CIAP1/2 in murine models of renal IRI, acute oxalate nephropathy and cisplatin nephropathy suggest the involvement of necroptosis as the main mechanism of acute tubular necrosis (ATN) despite different triggers of injury–for example, hypoxia, calcium oxalate crystals and a toxic chemical respectively.…”

Section: Discussionmentioning

confidence: 99%

“…RN and inflammation can induce each other in an auto-amplification loop of necroinflammation resulting in exaggerated cell death and inflammation that may lead to organ failure [23–25]. Since, most experiments are conducted in mice the relevance for the human disease remains a concern, and discrepancies in organ-specific expression levels between species were previously shown for pattern recognition receptors (PRRs), C-type lectins and TLR accessory molecules [26–31].…”

Section: Introductionmentioning

confidence: 99%

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Regulated necrosis-related molecule mRNA expression in humans and mice and in murine acute tissue injury and systemic autoimmunity leading to progressive organ damage, and progressive fibrosis

et al. 2016

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The species-specific, as well as organ-specific expression of regulated necrosis (RN)-related molecules, is not known. We determined the expression levels of tumour necrosis factor receptor-1 (TNFR1), receptor activated protein kinase (RIPK)1, RIPK3, mixed lineage kinase domain-like (MLKL), CASP8, Fas-associated protein with death domain (FADD), cellular inhibitor of apoptosis protein (CIAP)1, CIAP2, glutathione peroxidase-4 (GPX4), cyclophilin D (CYPD), CASP1, NLRP3 and poly(ADP-ribose) polymerase-1 (PARP1) in human and mouse solid organs. We observed significant differences in expression of these molecules between human and mice. In addition, we characterized their expression profiles in acute as well as persistent tissue injury and chronic tissue remodelling using acute and chronic kidney injury models. We observed that the degree and pattern of induction of RN-related molecules were highly dependent on the trigger and disease pathogenesis. Furthermore, we studied their expression patterns in mice with lupus-like systemic autoimmunity, which revealed that the expression of MLKL, GPX4 and PARP1 significantly increased in the spleen along disease progression and CASP1, RIPK1, RIPK3 and CYPD were higher at the earlier stages but were significantly decreased in the later stages. In contrast, in the kidney, the expression of genes involved in pyroptosis, e.g. NLRP3 and CASP1 were significantly increased and TNFR1, RIPK1, RIPK3, CIAP1/2 and GPX4 were significantly decreased along the progression of lupus nephritis (LN). Thus, the organ- and species-specific expression of RN-related molecules should be considered during designing experiments, interpreting the results as well as extrapolating the conclusions from one species or organ to another species or organ respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulated necrosis-related molecule mRNA expression in humans and mice and in murine acute tissue injury and systemic autoimmunity leading to progressive organ damage, and progressive fibrosis

et al. 2016

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“…As mentioned earlier, crystal-induced cellular necrosis leads to the release of danger-associated molecular patterns, alarmins, histones, proteases, etc., which can also trigger inflammation via activating the Toll-like receptors (TLRs). Tubular cell necrosis promotes leukocyte influx in the kidney as well as complement activation, thus enhancing renal necroinflammation [24]. In addition, crystals also activate the NLRP3 inflammasome in renal phagocytes and induce secretion of mature IL-1β during crystalline nephropathy [33].…”

Section: Type 2 Crystalline Nephropathy: Intratubular Crystal Formationmentioning

confidence: 99%

Novel Insights into Crystal-Induced Kidney Injury

Mulay

Shi

et al. 2018

Kidney Dis

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Background: The entity of crystal nephropathies encompasses a spectrum of different kidney injuries induced by crystal-formed intrinsic minerals, metabolites, and proteins or extrinsic dietary components and drug metabolites. Depending on the localization and dynamics of crystal deposition, the clinical presentation can be acute kidney injury, progressive chronic kidney disease, or renal colic. Summary: The molecular mechanisms involving crystal-induced injury are diverse and remain poorly understood. Type 1 crystal nephropathies arise from crystals in the vascular lumen (cholesterol embolism) or the vascular wall (atherosclerosis) and involve kidney infarcts or chronic ischemia, respectively. Type 2 crystal nephropathies arise from intratubular crystal deposition causing obstruction, interstitial inflammation, and tubular cell injury. NLRP3 inflammasome and necroptosis drive renal necroinflammation in acute settings. Type 3 is represented by crystal and stone formation in the draining urinary tract, i.e., urolithiasis, causing renal colic and chronic obstruction. Key Messages: Dissecting the types of injury is the first step towards a better understanding of the pathophysiology of crystal nephropathies. Crystal-induced activation of the inflammasome and necroptosis, crystal adhesion, crystallization inhibitors, extratubulation, and granuloma formation are only a few of certainly many involved pathomechanisms that deserve further studies to eventually form the basis for innovative cures for these diseases.

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“…This vicious cycle is termed necroinflammation and is a hallmark of the early injury phase ( Fig. 1D ) [ 34 , 35 ]. Necroptosis is induced by tumor necrosis factor (TNF)-α and interferon-γ [ 36 ].…”

Section: The Immune System In the Early Injury Phase Of Atnmentioning

confidence: 99%

Immune mechanisms in the different phases of acute tubular necrosis

Kundert

Platen

Iwakura

et al. 2018

Kidney Res Clin Pract.

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Acute kidney injury is a clinical syndrome that can be caused by numerous diseases including acute tubular necrosis (ATN). ATN evolves in several phases, all of which are accompanied by different immune mechanisms as an integral component of the disease process. In the early injury phase, regulated necrosis, damage-associated molecular patterns, danger sensing, and neutrophil-driven sterile inflammation enhance each other and contribute to the crescendo of necroinflammation and tissue injury. In the late injury phase, renal dysfunction becomes clinically apparent, and M1 macrophage-driven sterile inflammation contributes to ongoing necroinflammation and renal dysfunction. In the recovery phase, M2-macrophages and anti-inflammatory mediators counteract the inflammatory process, and compensatory remnant nephron and cell hypertrophy promote an early functional recovery of renal function, while some tubules are still badly injured and necrotic material is removed by phagocytes. The resolution of inflammation is required to promote the intrinsic regenerative capacity of tubules to replace at least some of the necrotic cells. Several immune mechanisms support this wound-healing-like re-epithelialization process. Similar to wound healing, this response is associated with mesenchymal healing, with a profound immune cell contribution in terms of collagen production and secretion of profibrotic mediators. These and numerous other factors determine whether, in the chronic phase, persistent loss of nephrons and hyperfunction of remnant nephrons will result in stable renal function or progress to decline of renal function such as progressive chronic kidney disease.

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How Kidney Cell Death Induces Renal Necroinflammation

Cited by 45 publications

References 141 publications

Regulated necrosis-related molecule mRNA expression in humans and mice and in murine acute tissue injury and systemic autoimmunity leading to progressive organ damage, and progressive fibrosis

Regulated necrosis-related molecule mRNA expression in humans and mice and in murine acute tissue injury and systemic autoimmunity leading to progressive organ damage, and progressive fibrosis

Novel Insights into Crystal-Induced Kidney Injury

Immune mechanisms in the different phases of acute tubular necrosis

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