Regulated Cell Death in AKI

Linkermann, Andreas; Chen, Guochun; Dong, Guie; Kunzendorf, Ulrich; Krautwald, Stefan; Dong, Zheng

doi:10.1681/asn.2014030262

Cited by 435 publications

(404 citation statements)

References 175 publications

Supporting

Mentioning

392

Contrasting

Unclassified

Order By: Relevance

“…19 Our data cannot define the specific cell death pathway involved but clearly indicate that the accelerated loss of severely injured S3 segment cells was associated with a favorable subsequent outcome, suggesting that the persistence of compromised tubular cells led to maladaptive changes in repair and inflammation as observed on day 3. Additional research will be needed to dissect the underlying interdependence between autophagy, cell death dynamics, and secondary changes in the postinjurious tubular milieu.…”

Section: At This Early Time Atg5mentioning

confidence: 56%

Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments

Baisantry¹,

Bhayana²,

Rong³

et al. 2015

JASN

View full text Add to dashboard Cite

Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5 Dflox/Dflox ) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5 Dflox/Dflox kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD.

show abstract

Section: At This Early Time Atg5mentioning

confidence: 56%

Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments

Baisantry¹,

Bhayana²,

Rong³

et al. 2015

JASN

View full text Add to dashboard Cite

show abstract

“…1,11,20,21 However, the TUNEL assay is not specific for apoptosis and additionally detects other cell-death forms. 22,23 Importantly, both interventions, CIX and M-920, reduced glomerular cell death and in situ caspase-3/7 activity in this study, but the CIX inhibitor nevertheless failed to protect from dNP. Hence, although our results confirm the association of cell death, as detected by TUNEL, with dNP, they question the mechanistic relevance of glomerular cell death.…”

mentioning

confidence: 55%

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Shahzad

Bock

Al‐Dabet

et al. 2016

JASN

View full text Add to dashboard Cite

Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1b), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucosestressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.

show abstract

“…Parenchymal cell necrosis, but not apoptosis, which seems to be minimally involved in the pathogenesis of acute kidney injury (32), triggers the release of DAMPs, some of which can trigger regulated necrosis and therefore initiate a necroinflammatory feedback loop. In clinical routine, immunosuppression is a standard procedure, but an anti-cell death therapy does not exist apart from cyclosporine (5).…”

Section: Discussionmentioning

confidence: 99%

Synchronized renal tubular cell death involves ferroptosis

Linkermann

Skouta

Himmerkus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

842

804

View full text Add to dashboard Cite

Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, irondependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the firstin-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.

show abstract

Regulated Cell Death in AKI

Cited by 435 publications

References 175 publications

Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments

Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Synchronized renal tubular cell death involves ferroptosis

Contact Info

Product

Resources

About