Reviews

Recent Approaches to Targeting Canonical NFκB Signaling in the Early Inflammatory Response to Renal IRI

Reid, Shelby¹; Scholey, James W.^1,2

¹Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

²Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada

Correspondence: Dr. Shelby Reid, Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada. Email: [email protected]

JASN 32(9):p 2117-2124, September 2021. | DOI: 10.1681/ASN.2021010069

Free

Abstract

Ischemia Reperfusion Injury

AKI is a challenging clinical problem that affects up to 5% of hospitalized patients and results in significant morbidity and mortality.^{^1–3} Intrarenal causes account for the majority of clinical cases of AKI, with the primary causes being ischemic injury or nephrotoxic injury.^{^4–6} Nearly two-thirds of these cases are caused by ischemia reperfusion injury (IRI) due to renal hypoperfusion after surgery, hemorrhage, cardiogenic shock, or sepsis.^⁷ Accordingly, this review focuses on experimental studies of interventions in IRI.

IRI is a two-step phenomenon that first involves the restriction of renal blood flow followed by restoration of blood flow. Severity of damage of IRI is dependent upon the metabolic demands of the tissue, the duration of the ischemic insult, and the method and extent of reperfusion.^⁸ More prolonged periods of ischemia can lead to kidney cell death, limited recovery of renal function, and/or progression of interstitial fibrosis.^⁹^,^¹⁰ There are five phases in the pathogenesis of IRI: ischemic insult, reperfusion, inflammation, regeneration/repair, and fibrosis.^¹¹ The severity and length of the final three phases depend on the duration of the ischemic insult and the extent of reperfusion.^⁹^,^¹⁰

Inflammation after IRI

The innate immune response is activated after reperfusion almost immediately. Injured tissue releases damage-associated molecular patterns (DAMPs) that are recognized by pattern-recognition receptors (PRRs).^¹² The engagement of these receptors by DAMPs initiates the recruitment of circulating leukocytes to the site of injury.^⁸ Further, DAMPs can lead to activation of the classic, lectin, and alternative complement pathways.^¹¹ All three pathways converge on the production of C3 and the downstream products C3a, C3b, and C5a.^¹¹ The effector of complement activation, the membrane attack complex C5b-9, leads to cell lysis and injury.^¹³ In addition, C3a, C5a, and membrane attack complex C5b-9 activate endothelial cells leading to increased expression of endothelial adhesion molecules, cytokines, and chemokines promoting leukocyte recruitment and adhesion.^¹¹

Recruited neutrophils adhere to the endothelium and migrate into the tissue where they release proteases, reactive oxygen species, and proinflammatory cytokines including IL-4, IL-6, and TNFα.^⁸ Infiltrating macrophages produce chemokines including C-C motif ligand-2, -3, and -5 in response to dendritic cells that, in turn, activate T-lymphocytes and recruit adaptive immune cells.^¹⁴

Proximal tubule cells secrete proinflammatory cytokines, including TNFα, IL-6, and IL1β, and upregulate C-X-C motif chemokine 3 receptor on their membrane to further promote inflammatory cell trafficking into the kidney interstitium.^¹⁵ The damaged tubular epithelial cells also release heat-shock proteins and nonhistone chromatin binding protein high mobility group box 1 (HMGB1) that lead to the activation of toll-like receptors (TLRs) including TLR2, TLR4, and TLR7.^¹⁶ The binding of these ligands to TLRs activates signal transduction pathways that converge on NFκB.

The adaptive immune response follows the innate immune response typically after 4–7 days and is initiated by dendritic cells activated by hypoxia and hypotension.^¹⁷ In the setting of kidney transplantation, donor dendritic cells migrate to secondary lymphoid tissue and directly activate alloreactive T cells against donor MHC molecules.^¹⁸ This transfer of MHC molecules is also dependent on extracellular vesicles from donor dendritic cells that migrate from the graft to lymphoid tissues.^¹⁹ Once the adaptive immune response is activated, a large influx of competent lymphocytes and leukocytes leads to vascular congestion and further activation of the complement cascade.^²⁰

NFκB Signaling Pathway

The NFκB pathway is one of the primary intracellular signaling pathways activated after inflammation.^²¹ NFκB is a family of transcription factors that regulate the expression of numerous genes involved in inflammation.^²² The NFκB family is composed of five members: NFκB1 (p50), NFκB2 (p52), RelA (p65), RelB, and c-Rel.^²³ In resting state, these transcription factors are sequestered in the cytoplasm through binding to the inhibitory protein, IκBα.

NFκB Signaling and IRI

In the setting of IRI, NFκB plays a key role in modulating the immune response after IRI.^²¹^,^²⁴ NFκB is activated after IRI by an array of stimuli, including PRRs and cytokines as well as TLRs, B-cell receptors, and T-cell receptors (Figure 1A).^²⁵ The activation leads to ubiquitin-dependent degradation of the inhibitor protein, IκBα, through phosphorylation by the IκK complex (composed of IKKα, IKKβ, and IKKγ).^²²^,^²⁶ The degradation of IκBα results in nuclear translocation of the canonical NFκB members (p50/RelA and p50/c-Rel dimers) where they stimulate the transcription of proinflammatory genes such as TNFα, IL-1, and IL-6 as well as many chemokines including C-C motif ligand-2 and CXCL2.^{^26–28} Cytokines and PRRs produced through NFκB signaling can form positive feedback loops.^²⁹ TNFα, for example, is widely produced after IRI through NFκB signaling, and, after production, can in turn stimulate NFκB signaling in a positive feedback manner.^²⁹

The activation of the NFκB signaling pathway plays a key role in the immune response in many types of acute kidney disease and CKD.^²¹ Although this review focuses on IRI, NFκB signaling has been implicated in experimental models of CKD including unilateral ureteral obstruction and diabetic nephropathy.^³⁰^,^³¹ Moreover, IRI is also associated with important long-term outcomes including CKD and ESKD and the effect of early blockade of NFκB on this later phase of injury should also be the focus of future studies.^{^32–34}

Targeting NFκB in IRI

Recent studies have demonstrated beneficial effects of inhibiting NFκB-mediated gene expression on the early phase of inflammation after IRI (Supplemental Table 1). Interventions can target NFκB at three levels: receptors that lead to NFκB activation, NFκB in the cytoplasm, and NFκB in the cell nucleus. Each approach ultimately leads to the inhibition of NFκB-mediated transcription of downstream target genes. However, IRI is a complex process that involves the activation of multiple signaling cascades and the effect of any intervention will likely affect many different pathways.^{^35–40} Accordingly, the effects of interventions on IRI may be due, at least in part, to blockade of pathways other than NFκB.

Targeting Receptors Leading to NFκB Activation

After IRI, injured cells release DAMPs which are recognized by PRRs leading to the activation of inflammatory pathways of innate immunity.^⁴¹ TLRs are one of the primary families of PRRs and are type I transmembrane glycoproteins found in the cell surface and also in the intracellular membranes.^⁴² These receptors recognize a variety of DAMPs including HMGB1, S100 proteins, and heat-shock proteins leading to the activation of the myeloid differentiation factor 88 (MyD88) signaling pathway, the toll/interferon response factor signaling pathway, and the NFκB signaling pathway, among others.^⁴²^,^⁴³

Genetic approaches can target upstream receptors that converge on the NFκB signaling pathway (Figure 1B).^⁴⁴^,^⁴⁵ Hu et al. silenced myeloid differentiation protein 2, a secretory glycoprotein that activates TLR4.^⁴⁴ After IRI, siMD-2 mice had improved kidney function, less histologic injury, and reduced expression of TNF-α, IL-6, and MCP-1.^⁴⁴In vitro studies confirmed siMD-2 decreased expression of tumor necrosis factor receptor–associated factor 6 by targeting TLR4, leading to a decrease in NFκB activation.^⁴⁴ Teng et al. took a similar approach and silenced src homology 2 domain–containing protein tyrosine phosphatase 2 (SHP-2), which regulates TLR4/NFκB signaling pathway.^{^45–47} Protein expression of TLR4 and NFκB and the downstream targets IL-6 and TNF-α decreased in primary renal epithelial tubular cells from rats collected after IRI treated with lentivirus vectors containing SHP-2–silencing RNA compared with control cells.^⁴⁵

Investigators have also taken a pharmacologic approach to target upstream receptors that converge on NFκB signaling (Figure 1B).^⁴⁸^,^⁴⁹ Zhang et al. explored the effects of dexamethasone, a glucocorticoid known to regulate MAPK signaling, in the setting of IRI.^⁴⁸^,^⁵⁰ Dexamethasone administered before IRI in mice led to improved renal function, reduced expression of HMGB1 and TLR4, reduced activation of NFκB, and reduced expression of TNF-α, IL-1β, and IL-6.^⁴⁸ Jun et al. tested the effect of ethyl pyruvate, an intermediate of pyruvate that has been shown to target HMGB1, in the setting of hyperglycemia and IRI.^⁴⁹^,^⁵¹ Ethyl pyruvate administered either before or after IRI in hyper- and normal-glycemic rats led to reduced expression of HMGB1 and TLR4, reduced activation of NFκB, and reduced expression of TNF-α and IL-1β to similar extents in all treatment groups.^⁴⁹

Other groups have directly targeted TLRs with the intent of downstream regulation of NFκB.^{^52–56} Yayi et al. explored the role of TLRs in the setting of diabetes and IRI.^⁵² Chloroquine, an inhibitor of TLRs, was administered before IRI in diabetic rats.^⁵²^,^⁵⁷ TLR inhibition improved kidney function and reduced expression of TLR7, MyD88, and NFκB.^⁵² Li et al. examined the effects of resveratrol, a compound found in berries and red wine, with antioxidant and anti-inflammatory properties.^⁵³^,^⁵⁸ Resveratrol administered to rats before IRI led to improved kidney function, reduced oxidative stress, and reduced expression of TLR4, MyD88, IKKα, p-IκBα, and p-NFκB.^⁵³ Sun et al. explored whether salidroside, a phenylpropanoid glycoside with anti-inflammatory properties, could alleviate injury in an in vitro hypoxia-reoxygenation model.^⁵⁴^,^⁵⁹ Salidroside treatment before hypoxia-reoxygenation led to improved cell viability as well as reduced expression of TLR4 and p-65.^⁵⁴ Downstream NFκB targets including TNF-α, IL-1β, and IL-6 decreased in a dose-dependent manner.^⁵⁴ Su et al. targeted GSK-3β, an enzyme that plays a key role in cell proliferation and differentiation, including that of the renal epithelium.^⁵⁵^,^⁶⁰^,^⁶¹ Pharmacologically targeting GSK-3β in a model of renal IRI led to improved kidney function; reduced expression of p-IκB, TLR4, MyD88, and p-p65; and downstream expression of TNF-α, IL-1β, and IL-6, suggesting overall downregulation of TLR/MyD88/NFκB pathways.^⁵⁵ Finally, Qiu et al. examined the effects of MaR1, a proresolving lipid mediator produced by macrophages on renal IRI.^⁵⁶^,^⁶² After IRI, MaR1 led to improved renal function and reduced expression of TLR4 and NFκB.^⁵⁶

In summary, both genetic and pharmacologic inhibition of cell membrane receptors that converge on NFκB attenuate IRI-induced inflammation. However, targeting the NFκB pathway upstream may lead to unintended downstream effects. Intracellular targeting of NFκB may be more precise when it comes to the inhibition of inflammation.

Targeting NFκB in the Cytoplasm

Downstream of receptors, the cytoplasmic inhibitor protein IκBα is degraded in a ubiquitin-dependent manner after phosphorylation by the IκK complex.^²²^,^²⁶ Recent studies have targeted these steps of the NFκB signaling pathway in specific cell populations (Figure 1C).^⁶³^,^⁶⁴ Marko et al. generated mice expressing the NFκB repressor IκBαΔN in renal epithelial cells and studied renal epithelial NFκB activity after IRI.^⁶³ The transgenic mice exhibited better kidney function and reduced expression of NFκB-dependent genes.^⁶³ Yamashita et al. generated podocyte-specific IκBΔN mice^⁶⁴; however, podocyte-specific NFκB inhibition had no effect on inflammation after IRI because renal function and injury were similar in both transgenic and wild-type mice.^⁶⁴

Other groups have focused on targeting IκK complex activation (Figure 1C).^⁶⁵^,^⁶⁶ Johnson et al. administered IKK16, an IκK complex inhibitor, to rats 24 hours after IRI.^⁶⁵^,^⁶⁷ IKK16 improved kidney function, reduced activation of IκK, and decreased NFκB activation.^⁶⁵ Amrouche et al. examined the role of miR-146a, an NFκB-dependent microRNA that forms a negative feedback loop to limit inflammatory responses to NFκB.^⁶⁶^,^⁶⁸ miR-146a limited the inflammatory response after IRI and also reduced the severity of tissue injury. In accord with these observations, mir-146a knock-out mice were more susceptible to IRI.^⁶⁶ Interestingly, mir-146a expression led to the downregulation of IL-1 receptor–associated kinase 1, which is involved in the activation of the IκK complex.^⁶⁶^,^⁶⁹

As an alternative approach, some groups have targeted NFκB activation by focusing on specific subunits of the IκK complex (Figure 1C).^{^70–74} Rabadi et al. studied peptidyl arginine deiminase–4 (PAD4), an enzyme involved in the catalytic conversion of peptidyl-arginine residues to peptidyl-citrulline.^{^70–72}^,^⁷⁵ PAD4-deficient mice had improved kidney function over sham mice after IRI, and recombinant treatment with PAD4 led to increased nuclear translocation of NFκB.^⁷⁰ In a follow-up study, Rabadi et al. demonstrated that PAD4 preferentially citrullinates IKKγ (also known as NFκB essential modulator [NEMO]), as opposed to the other members of IκK complex, promoting NFκB activation.^⁷¹ Furthermore, targeting NEMO with an NEMO-binding peptide attenuated PAD4-mediated injury after IRI and attenuated NFκB activation.^⁷¹ Most recently, this group reported that proximal tubule cell NEMO is a critical driver of IRI because proximal tubule–NEMO–deficient mice and proximal tubule–NEMO–binding peptide treatment showed improved kidney function and reduced NFκB activation after IRI compared with wild-type mice.^⁷²

Wei et al. also targeted NEMO by using zinc finger A20 transfection in rats.^⁷³ A20 is an NFκB-dependent gene that forms a negative feedback loop to limit NFκB-mediated inflammation through binding to NEMO and preventing IκK activation.^⁷⁶ A20 overexpression in rats subjected to IRI led to improved renal function and decreased NFκB activation.^⁷³ Guo et al. looked at another member of the IκK complex, IKKβ (also known as IKK2), in lymphocytes.^⁷⁴ Interestingly, NEMO- and IKK2-lymphocyte knockout mice had worsened kidney function after IRI compared with wild-type mice, potentially due to a decrease in regulatory T cells.^⁷⁴ However, the administration of a specific IKK2 inhibitor before IRI in wild-type mice improved kidney function.^⁷⁴ The data suggested that systemic IKK2 inhibition targets renal epithelial cells as opposed to lymphocytes.^⁷⁴

Although these studies demonstrate that targeting NFκB signaling within the cytoplasm may be beneficial, they also highlight the challenges surrounding complete knockdown of a signaling cascade that is involved in several key cellular processes. Furthermore, these studies also suggest that cell-specific knockdown of NFκB may be more beneficial. However, the timing of NFκB blockade is not well understood.

Targeting NFκB in the Nucleus

Investigators have also explored the effects of targeting NFκB within the nucleus after IRI (Figure 1D).^²⁴^,^{^77–80} Ubiquitination of IκBα and its subsequent degradation lead to the nuclear translocation of canonical NFκB transcription factors where they bind to NFκB consensus sequences in gene promoter regions to stimulate gene transcription.^²² In this regard, Zhang et al. explored the role of miR-181d in NFκB activation.^⁷⁷ miR-181d-5p overexpression reduced NFκB activation and improved kidney function after IRI.^⁷⁷ Bioinformatic analysis and follow-up experiments demonstrated that miR-181d-5p targets krueppel-like factor 6, an NFκB cofactor that aids in the binding of p65 to the promoter region.^⁷⁷^,^⁸¹ Park et al. investigated small heterodimer partner (SHP), which acts as a transcriptional coregulator by repressing the transactivation of p65.^⁷⁸^,^⁸² After IRI, SHP mRNA and protein expression were reduced. In vitro, SHP transfection into kidney epithelial cells improved cell viability, reduced oxidative stress, and reduced NFκB activation after treatment with hydrogen peroxide.^⁷⁸

The acetylation of RelA at lysine-310 results in enhanced transcriptional activity of NFκB.^⁸³ This is mediated by the binding of bromodomain-containing protein 4 (BRD4) to the acetylated lysine-310 facilitating assembly of the transcriptional apparatus, including p-TEFb complex and RNA polymerase II.^⁸³ Liu et al. studied the effects of JQ1, a BRD4 inhibitor originally designed for cancer treatment.^⁷⁹^,^⁸³ JQ1 administration before IRI improved renal function and reduced kidney injury.^⁷⁹ Similarly, Reid et al. studied the effects of MS417, a BRD4-specific inhibitor designed to inhibit BRD4 from interacting with RelA, thus inhibiting NFκB-mediated transcription.^²⁴^,^⁸⁴ After IRI, mice treated with MS417 had reduced recruitment and activation of neutrophils in the kidney tissue and reduced tubular injury.^²⁴ In another approach, Zhao et al. treated rats with total flavonoids which activate silent information regulator factor 2–related enzyme 1 (sirt1), a histone deacetylase that targets RelA at lysine 310 in the nucleus.^⁸⁰^,^⁸⁵ Sirt1 activation improved kidney function and led to the downregulation of NFκB and its target genes TNFα and IL1β.^⁸⁰

Targeting NFκB transactivation or acetylation within the nucleus offers a promising strategy for the downregulation of NFκB-mediated gene expression. Further, the development of BRD4 inhibitors for cancer therapies,^⁸⁴^,^⁸⁶ and their availability for use in humans, increases the potential for translational studies. However, particular considerations are required in regard to BRD4 inhibitors because these compounds may have broader effects on gene expression beyond the inhibition of NFκB.^²⁴^,^{^87–89}

Future Directions

Inflammation plays a critical role in both tissue injury and the resolution of injury.^⁹⁰ Therefore, complete inhibition of NFκB may have deleterious consequences^⁷⁴ and a protocol that is time-limited should be investigated. Translation of studies limited to specific phases of IRI will likely be limited to clinical settings where AKI is an expected and common complication. For example, this has been described in cases of cisplatin-induced nephrotoxicity where pretreatment protocols reduce oxidative stress and inflammation^{^91–93} and in the setting of aortic aneurysm repair.^⁹⁴

Despite recent advances in our understanding of the mechanisms responsible for IRI, few therapeutic strategies have emerged. A key limitation of the current data is the continual use of male animals notwithstanding the fact that sexual dimorphism has been shown to play a critical role in AKI. Both animal and human studies have demonstrated protection within the female sex against IRI which may be due to the regulation of inflammatory cellular pathways by sex hormones.^{^95–98} It was recently reported that the expression of genes related to TNFα signaling, an essential regulator of NFκB, was lower in kidneys of female mice compared with male mice after IRI.^⁹⁸ Future studies should take these findings into account and examine interventions in both female and male sexes.

Another limitation of the current data is the primary use of rodent models which may limit the ability to translate findings to humans.^⁹⁹^,^¹⁰⁰ Transcriptomic responses to inflammatory stressors in murine models differ dramatically from humans, suggesting that biology may contribute significantly to the challenge of translation.^¹⁰¹ In order to address this, it may be important to use more relevant models that readily translate clinically. This may require the use of porcine models of IRI, or clinical settings where AKI is a common complication.^⁹⁴^,^¹⁰²

Conclusions

NFκB is an attractive treatment target for IRI. Several experimental approaches have been taken ranging from nonspecific blockade of NFκB activation to more specific effects on components of the NFκB signaling cascade and transcriptional activation. Future work should aim to better define the timing of interventions designed to limit IRI-induced injury and focus on translation. The translation of experimental studies to human kidney injury is particularly challenging and will likely require careful selection of the setting and cause of IRI.

Disclosures

All authors have nothing to disclose.

Funding

S. Reid is supported by the Queen Elizabeth II Graduate Scholarships in Science and Technology. J.W. Scholey is supported by the Canadian Institutes of Health Research (126014). J.W. Scholey reports receiving an unrestricted Research Grant from Amgen Canada Incorporated, matching funding for a CIHR SPOR grant (CanSOLVE CKD).

Published online ahead of print. Publication date available at www.jasn.org.

Acknowledgments

Dr. Shelby Reid wrote the manuscript; and Dr. Shelby Reid and Dr. James W. Scholey contributed equally to reviewing literature, and reviewing and editing the manuscript.

Supplemental Material

This article contains the following supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2021010069/-/DCSupplemental.

Supplemental Table 1. Manuscripts targeting NFκB published in the last 5 years.

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Keywords:

ischemia-reperfusion; NF kappaB; inflammation

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Recent Approaches to Targeting Canonical NFκB Signaling in the Early Inflammatory Response to Renal IRI

Abstract

Ischemia Reperfusion Injury

Inflammation after IRI

NFκB Signaling Pathway

NFκB Signaling and IRI

Targeting NFκB in IRI

Targeting Receptors Leading to NFκB Activation

Targeting NFκB in the Cytoplasm

Targeting NFκB in the Nucleus

Future Directions

Conclusions

Disclosures

Funding

Acknowledgments

Supplemental Material

References

Article Keywords

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Recent Approaches to Targeting Canonical NFκB Signaling in the Early Inflammatory Response to Renal IRI : Journal of the American Society of Nephrology

Abstract

Ischemia Reperfusion Injury

Inflammation after IRI

NFκB Signaling Pathway

NFκB Signaling and IRI

Targeting NFκB in IRI

Targeting Receptors Leading to NFκB Activation

Targeting NFκB in the Cytoplasm

Targeting NFκB in the Nucleus

Future Directions

Conclusions

Disclosures

Funding

Acknowledgments

Supplemental Material

References