Anaritide in Acute Tubular Necrosis

Allgren, Robin L.; Marbury, Thomas; Rahman, Sahinur; Weisberg, Lawrence S.; Fenves, Andrew Z.; Lafayette, Richard A.; Sweet, Richard; Genter, F. C.; Kurnik, Brenda R.C.; Conger, John D.; Sayegh, Mohamed H.

doi:10.1056/nejm199703203361203

Cited by 404 publications

(101 citation statements)

References 18 publications

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“…[28][29][30][31] Although inhibition of p53 activation suppresses apoptosis, it may have no effect on primary necrosis. It should, however, reduce secondary necrosis, which is known to occur after apoptosis.…”

Section: Discussionmentioning

confidence: 99%

UNC5B Receptor Deletion Exacerbates Tissue Injury in Response to AKI

Ranganathan

Jayakumar

Navankasattusas

et al. 2014

Journal of the American Society of Nephrology

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Netrin-1 regulates cell survival and apoptosis by activation of its receptors, including UNC5B. However, the in vivo role of UNC5B in cell survival during cellular stress and tissue injury is unknown. We investigated the role of UNC5B in cell survival in response to stress using mice heterozygously expressing the UNC5B gene (UNC5B 2/flox ) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B 2/flox/GGT-cre ). Mice were subjected to two different models of organ injury: ischemia reperfusion injury of the kidney and cisplatin-induced nephrotoxicity. Both mouse models of UNC5B depletion had normal organ function and histology under basal conditions. After AKI, however, UNC5B 2/flox/GGT-cre mice exhibited significantly worse renal function and damage, increased tubular apoptosis, enhanced p53 activation, and exacerbated inflammation compared with UNC5B 2/flox and wild-type mice. shRNA-mediated suppression of UNC5B expression in cultured tubular epithelial cells exacerbated cisplatin-induced cell death in a p53-dependent manner and blunted Akt phosphorylation. Inhibition of PI3 kinase similarly exacerbated cisplatin-induced apoptosis; in contrast, overexpression of UNC5B reduced cisplatin-induced apoptosis in these cells. Taken together, these results show that the netrin-1 receptor UNC5B plays a critical role in cell survival and kidney injury through Akt-mediated inactivation of p53 in response to stress.

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Section: Discussionmentioning

confidence: 99%

UNC5B Receptor Deletion Exacerbates Tissue Injury in Response to AKI

Ranganathan

Jayakumar

Navankasattusas

et al. 2014

Journal of the American Society of Nephrology

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“…Administration of ANP exerted beneficial effects in experimental and clinical acute renal failure [20,21]. We generated hypotensive transgenic mice overexpressing the mouse gene encoding BNP (Nppb) in the liver (BNP-Tg mice), which showed more than a 100-fold increase in plasma BNP and constitutive elevation of urinary guanosine 3′,5′-cyclic monophosphate (cGMP) levels [22].…”

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confidence: 99%

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

et al. 2006

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Aims/hypothesis Brain natriuretic peptide (BNP) is a potent vasorelaxing and natriuretic peptide that is secreted from the heart and has cardioprotective properties. We have previously generated hypotensive transgenic mice (BNP-Tg mice) that overproduce BNP in the liver, which is released into the circulation. Using this animal model, we successfully demonstrated the amelioration of renal injury after renal ablation and in proliferative glomerulonephritis. Glomerular hyperfiltration is an early haemodynamic derangement, representing one of the key mechanisms of the pathogenesis of diabetic nephropathy. Based on the suggested involvement of increased endogenous natriuretic peptides, the aim of this study was to investigate their role in the development and progression of diabetic nephropathy. Materials and methods We evaluated the progression of renal injury and fibrogenesis in BNP-Tg mice with diabetes induced by streptozotocin. We also investigated the effect of BNP on high glucose-induced signalling abnormalities in mesangial cells. Results After induction of diabetes, control mice exhibited progressively increased urinary albumin excretion with impaired renal function, whereas these changes were significantly ameliorated in BNP-Tg mice. Notably, diabetic BNP-Tg mice revealed minimal mesangial fibrogenesis with virtually no glomerular hypertrophy. Glomerular upregulation of extracellular signal-regulated kinase, TGF-β and extracellular matrix proteins was also significantly inhibited in diabetic BNP-Tg mice. In cultured mesangial cells, activation of the above cascade under high glucose was abrogated by the addition of BNP. Conclusions/interpretation Chronic excess of BNP prevents glomerular injury in the setting of diabetes, suggesting that renoprotective effects of natriuretic peptides may be therapeutically applicable in preventing the progression of diabetic nephropathy.

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“…In conclusion, low-dose dopamine is not recommended for patients with CIN as it does not prevent the progression of kidney dysfunction. In a RCT of critically ill patients with AKI, including patients with CIN, the dialysis-free survival for 21 days after treatment, percentage of patients undergoing dialysis by day 14, and all-cause mortality by day 21 did not differ significantly between patients receiving high-dose hANP at 0.2 lg/kg/min for 24 h or those receiving placebo [186]. In a RCT of critically ill patients with oliguric AKI, the dialysisfree survival through day 21, percentage of patients undergoing dialysis by day 14, and mortality through day 60 did not differ significantly between patients receiving hANP and placebo [187].…”

Section: Level Of Evidence: I Grade Of Recommendation: D Rationale Cqmentioning

confidence: 93%