scholarly journals p53 regulates renal expression of HIF-1α and pVHL under physiological conditions and after ischemia-reperfusion injury

2008 ◽  
Vol 295 (6) ◽  
pp. F1666-F1677 ◽  
Author(s):  
Timothy A. Sutton ◽  
Jared Wilkinson ◽  
Henry E. Mang ◽  
Nicole L. Knipe ◽  
Zoya Plotkin ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Microvascular Damage ◽  
Von Hippel Lindau ◽  
Physiological Conditions ◽  
Collecting Tubules ◽  
Opposing Effects

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and is characterized by widespread tubular and microvascular damage. The tumor suppressor p53 is upregulated after IRI and contributes to renal injury in part by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-α conveys significant protection after IRI. The hypoxia-inducible factor-1 (HIF-1) pathway is also activated after IRI and has opposing effects to those promoted by p53. The balance between the HIF-1 and p53 responses can determine the outcome of IRI. In this manuscript, we investigate whether p53 regulates the HIF-1 pathway in a rodent model of IRI. HIF-1α is principally expressed in the collecting tubules (CT) and thick ascending limbs (TAL) under physiological conditions. However, inhibition of p53 with pifithrin-α increases the faint expression of HIF-1α in proximal tubules (PT) under physiological conditions. Twenty-four hours after IRI, HIF-1α expression is decreased in both CT and TAL. HIF-1α expression in the PT is not significantly altered after IRI. Acute inhibition of p53 significantly increases HIF-1α expression in the PT after IRI. Additionally, pifithrin-α prevents the IRI-induced decrease in HIF-1α in the CT and TAL. Parallel changes are observed in the HIF-1α transcriptive target, carbonic anhydrase-9. Finally, inhibition of p53 prevents the dramatic changes in Von Hippel-Lindau protein morphology and expression after IRI. We conclude that activation of p53 after IRI mitigates the concomitant activation of the protective HIF-1 pathway. Modulating the interactions between the p53 and HIF-1 pathway can provide novel options in the treatment of AKI.

Abstract 193: Antithrombin Perfluorocarbon Nanoparticles Ameliorate Renal Injury Following Transient Warm Ischemia

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Chandu Vemuri ◽  
Junjie Chen ◽  
Rohun U Palekar ◽  
John S Allen ◽  
Xiaoxia Yang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Warm Ischemia ◽  
P Value ◽  
Sprague Dawley ◽  
Histologic Analysis ◽  
Microvascular Thrombosis

Objective: Thrombin mediated microvascular thrombosis plays a crucial role in the pathogenesis of acute renal reperfusion injury following transient ischemia. We hypothesize that anti-thrombin nanoparticles will ameliorate acute renal injury by inhibiting microvascular thrombosis. Methods: Adult, male Sprague Dawley rats were randomized into two groups of 5 to receive tail vein injections of saline or nanoparticles loaded with Phe[D]-Pro-Arg-Chloromethylketone (NP-PPACK). Immediately following injection, all animals underwent operative bilateral renal artery occlusion to create 45 minutes of warm ischemia, followed by restoration of renal blood flow. Blood samples were drawn daily and animals were euthanized on day 1 or 7 for histologic analysis of kidney injury (H&E, TUNEL and thrombin staining). Results: Histologic analysis of renal tissue revealed significant apoptosis, necrosis and thrombin accumulation 1 day after ischemia-reperfusion, confirming acute kidney injury. The peak creatinine (mg/dl) on day 1 was significantly lower in NP-PPACK treated animals (0.57 +/- 0.07 (SEM)) than in saline treated controls (1.40 +/- 0.20 (SEM); p-value <0.01). Furthermore, animals treated with NP-PPACK continued to exhibit less renal dysfunction for 7 days after injury (Figure 1). Conclusion: Histologically confirmed intrarenal thrombosis was detected one day after ischemia-reperfusion injury. Targeted inhibition of thrombin with NP-PPACK prevented a decline in renal function following transient occlusion. Future work will focus on defining the underlying mechanisms of this effect.

scholarly journals Targeting HIF-1α to Prevent Renal Ischemia-Reperfusion Injury: Does It Work?

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Kapil Sethi ◽  
Kenny Rao ◽  
Damien Bolton ◽  
Oneel Patel ◽  
Joseph Ischia
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Arterial Occlusion ◽  
Small Animal ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Metabolic Adaptation ◽  
Critical Ischemia

Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal tissue. Prolonged renal ischemia may lead to irreversible nephron damage in the remaining tissue and, ultimately, chronic kidney disease. This is potentiated by the incompletely understood ischemia-reperfusion injury (IRI). A key mechanism in IRI prevention appears to be the upregulation of an intracellular transcription protein, Hypoxia-Inducible Factor (HIF). HIF mediates metabolic adaptation, angiogenesis, erythropoiesis, cell growth, survival, and apoptosis. Upregulating HIF-1α via ischemic preconditioning (IPC) or drugs that simulate hypoxia (hypoxia-mimetics) has been investigated as a method to reduce IRI. While many promising chemical agents have been trialed for the prevention of IRI in small animal studies, all have failed in human trials. The aim of this review is to highlight the techniques and drugs that target HIF-1α and ameliorate IRI associated with renal ischemia. Developing a technique or drug that could reduce the risk of acute kidney injury associated with renal IRI would have an immediate worldwide impact on multisystem surgeries that would otherwise risk ischemic tissue injury.

scholarly journals Lymphocyte-specific deletion of IKK2 or NEMO mediates an increase in intrarenal Th17 cells and accelerates renal damage in an ischemia-reperfusion injury mouse model

2016 ◽  
Vol 311 (5) ◽  
pp. F1005-F1014 ◽  
Author(s):  
Linlin Guo ◽  
Hannah Heejung Lee ◽  
María de las Mercedes Noriega ◽  
Hans J. Paust ◽  
Gunther Zahner ◽  
...  
Keyword(s):  
Renal Disease ◽  
Serum Creatinine ◽  
Reperfusion Injury ◽  
Th17 Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
T Cell Response ◽  
Time Points ◽  
Specific Deletion

Acute kidney injury (AKI) is associated with poor patient outcome and a global burden for end-stage renal disease. Ischemia-reperfusion injury (IRI) is one of the major causes of AKI, and experimental work has revealed many details of the inflammatory response in the kidney, such as activation of the NF-κB pathway. Here, we investigated whether deletion of the NF-κB kinases IKK2 or NEMO in lymphocytes or systemic inhibition of IKK2 would cause different kidney inflammatory responses after IRI induction. Serum creatinine, blood urea nitrogen (BUN) level, and renal tubular injury score were significantly increased in CD4creIKK2f/f (CD4xIKK2Δ) and CD4creNEMOf/f (CD4xNEMOΔ) mice compared with CD4cre mice after IRI induction. The frequency of Th17 cells infiltrating the kidneys of CD4xIKK2Δ or CD4xNEMOΔ mice was also significantly increased at all time points. CCL20, an important chemokine in Th17 cell recruitment, was significantly increased at early time points after the induction of IRI. IL-1β, TNF-α, and CCL2 were also significantly increased in different patterns. A specific IKK2 inhibitor, KINK-1, reduced BUN and serum creatinine compared with nontreated mice after IRI induction, but the frequency of kidney Th17 cells was also significantly increased. In conclusion, although systemic IKK2 inhibition improved kidney function, lymphocyte-specific deletion of IKK2 or NEMO aggravated kidney injury after IRI, and, in both conditions, the percentage of Th17 cells was increased. Our findings demonstrate the critical role of the NF-κB pathway in Th17 activation, which advises caution when using systemic IKK2 inhibitors in patients with kidney injury, since they might impair the T cell response and aggravate renal disease.

scholarly journals Arginase-2 mediates renal ischemia-reperfusion injury

2017 ◽  
Vol 313 (2) ◽  
pp. F522-F534 ◽  
Author(s):  
Wesley M. Raup-Konsavage ◽  
Ting Gao ◽  
Timothy K. Cooper ◽  
Sidney M. Morris ◽  
W. Brian Reeves ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Blood Urea Nitrogen ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Arginase Activity ◽  
Urea Nitrogen ◽  
The Impact ◽  
Novel Therapeutic

Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia-reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine 1) whether renal arginase activity or expression is increased in renal IRI, and 2) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (wild type) and arginase-2 (ARG2)-deficient ( Arg2−/−) mice subjected to bilateral renal ischemia for 28 min, followed by reperfusion for 24 h. ARG2 expression and arginase activity significantly increased following renal IRI, paralleling the increase in kidney injury. Pharmacological blockade or genetic deficiency of Arg2 conferred kidney protection in renal IRI. Arg2−/− mice had significantly attenuated kidney injury and lower plasma creatinine and blood urea nitrogen levels after renal IRI. Blocking arginases using S-(2-boronoethyl)-l-cysteine (BEC) 18 h before ischemia mimicked arginase deficiency by reducing kidney injury, histopathological changes and kidney injury marker-1 expression, renal apoptosis, kidney inflammatory cell recruitment and inflammatory cytokines, and kidney oxidative stress; increasing kidney nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation, kidney peroxisome proliferator-activated receptor-γ coactivator-1α expression, and mitochondrial ATP; and preserving kidney mitochondrial ultrastructure compared with vehicle-treated IRI mice. Importantly, BEC-treated eNOS-knockout mice failed to reduce blood urea nitrogen and creatinine following renal IRI. These findings indicate that ARG2 plays a major role in renal IRI, via an eNOS-dependent mechanism, and that blocking ARG2 activity or expression could be a novel therapeutic approach for prevention of AKI.

Molecular Mechanisms of Renal Ischemic Conditioning Strategies

2015 ◽  
Vol 55 (3) ◽  
pp. 151-183 ◽  
Author(s):  
Casper Kierulf-Lassen ◽  
Gertrude J. Nieuwenhuijs-Moeke ◽  
Nicoline V. Krogstrup ◽  
Mihai Oltean ◽  
Bente Jespersen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Clinical Settings ◽  
Ischemic Conditioning ◽  
Protective Signaling ◽  
Survival Mechanisms

Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized.

scholarly journals Beclin 1/Bcl-2 complex-dependent autophagy activity modulates renal susceptibility to ischemia-reperfusion injury and mediates renoprotection by Klotho

2020 ◽  
Vol 318 (3) ◽  
pp. F772-F792 ◽  
Author(s):  
Peng Li ◽  
Mingjun Shi ◽  
Jenny Maique ◽  
Joy Shaffer ◽  
Shirley Yan ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Genetic Manipulation ◽  
Protein Complexes ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Beclin 1 ◽  
Klotho Protein ◽  
And Function ◽  
Autophagy Activity

Klotho- and beclin 1-driven autophagy extends life. We examined the role of beclin 1 in modifying acute kidney injury (AKI) and whether beclin 1 mediates Klotho’s known renoprotective action in AKI. AKI was induced by ischemia-reperfusion injury in mice with different levels of autophagy activity by genetic manipulation: wild-type (WT) mice with normal beclin 1 expression and function, mice with normal beclin 1 levels but high activity through knockin of gain-of-function mutant beclin 1 ( Becn1F121A), mice with low beclin 1 levels and activity caused by heterozygous global deletion of beclin 1 ( Becn1+/−), or mice with extremely low beclin 1 activity from knockin of the mutant constitutively active beclin 1 inhibitor Bcl-2 ( Bcl2AAA). Klotho was increased by transgenic overexpression ( Tg-Kl) or recombinant Klotho protein administration. After ischemia-reperfusion injury, Becn1F121A mice (high autophagy) had milder AKI and Becn1+/− and Bcl2AAA mice (low autophagy) had more severe AKI than WT mice. Tg-Kl mice had milder AKI, but its renoprotection was partially attenuated in Becn1+/− ;Tg-Kl mice and was significantly reduced, although not completely abolished, in Bcl2AAA;Tg-Kl mice. Recombinant Klotho protein conferred more renoprotection from AKI in WT mice than in Becn1+/− or Bcl2AAA mice. Klotho reduced beclin 1/Bcl-2 protein complexes and increased autophagy activity, but this effect was less prominent in mice or cells with Bcl2AAA. Transfected Bcl2AAA or Becn1F123A decreased or increased autophagy activity and rendered cells more susceptible or more resistant to oxidative cytotoxicity, respectively. In conclusion, beclin 1 confers renoprotection by activating autophagy. Klotho protects the kidney partially via disruption of beclin 1/Bcl-2 interactions and enhancement of autophagy activity.

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