Growing evidence implicates diabetic tubulopathy (DT), driven by tubular atrophy and interstitial fibrosis, as a major determinant of renal insufficiency and disease outcome in diabetic kidney disease (DKD). This perspective underscores the need to elucidate tubular-specific pathogenic mechanisms. An emerging perspective suggests that mitochondrial dysfunction is an early event in DKD, although the precise pathological mechanism remains unknown. Our previous work identified glycogen synthase kinase 3 beta (GSK3 beta) as a potential novel biomarker for DKD. Thus, we further revealed that GSK3 beta was hyperactivated in the renal tubule of DKD, which was positively correlated with early mitochondrial dysfunction. Conversely, therapeutic targeting of GSK3 beta with TDZD-8 or genetic silencing attenuated early mitochondrial dysfunction and delayed DT. Mechanistically, the key downstream effector through which GSK3 beta accelerates DKD progression is the Transcription factor EB (TFEB) signaling pathway. Specifically, upon activation, GSK3 beta inhibits the nuclear translocation of TFEB, leading to dysregulated TFEB transcriptional function, which in turn mediates early mitochondrial damage in experimental models of DKD. This is manifested as alterations in mitochondrial morphology, dynamics, mitophagy, and reactive oxygen species production. Therefore, GSK3 beta overexpression accelerates early mitochondrial dysfunction in renal tubules during DKD by impairing TFEB nuclear translocation, providing a rationale for targeting the GSK3 beta/TFEB axis to preserve mitochondrial fitness in DT.

Melanocortin therapeutics, exemplified by adrenocorticotropic hormone, have a proven steroidogenic-independent anti-proteinuric and glomerular protective effect. The biological functions of melanocortins are mediated by melanocortin receptors (MCR), including MC1R, which recent studies have shown to protect against glomerular disease. However, the role of other MCRs like MC5R is unknown. Here, Mc5r knockout exacerbated glomerulopathy in mice injured by adriamycin (ADR) or nephrotoxic serum (NTS), as demonstrated by increased albuminuria and podocyte injury. Conversely, selective MC5R agonism using a peptidomimetic agonist improved outcomes of glomerulopathies. Mechanistically, MC5R is expressed in glomerular podocytes. Reconstitution of MC5R in podocytes attenuated glomerular injury and proteinuria in Mc5r knockout mouse models of glomerulopathies, indicating a direct podocyte protective effect. In vitro, MC5R agonism in primary wild-type podocytes attenuated ADR-elicited cytoskeleton disruption, hypermotility and apoptosis, associated with restored inhibitory phosphorylation of glycogen synthases kinase 3β (GSK3β), a signaling transducer downstream of MC5R and at the nexus of multiple podocytopathic pathways. In parallel, ADR-induced phosphorylation and activation of GSK3β substrates, such as paxillin and NF-κB Rela/p65, were abrogated, leading to improved actin cytoskeleton integrity and diminished expression of mediators of podocyte injury, like MCP-1, B7-1 and Cathepsin L. This protective effect of MC5R agonism was blunted in wild-type podocytes expressing constitutively active GSK3β and was mimicked in Mc5r knockout podocytes by ectopic expression of dominant negative GSK3β. Consistently in ADR-injured Mc5r knockout mice, worsened podocytopathy was associated with enhanced GSK3β hyperactivity. These findings suggest that MC5R signaling protects against podocyte injury and may serve as a novel therapeutic target for glomerular diseases.

BACKGROUND:Fistula stenosis is a primary contributor to arteriovenous fistula (AVF) failure in maintenance hemodialysis patients. Emerging data indicated excessive fibrotic remodeling was the primarily contributor to fistula stenosis during AVF remodeling. The mineralocorticoid receptor (MR) has been implicated in vascular remodeling across various cardiovascular pathologies. However, its role in AVF remodeling, particularly concerning fibrotic remodeling, remains elusive. METHODS:MR expression and the phenotypes of vascular smooth muscle cells (VSMC) were assessed in dysfunctional AVF. The effects of MR on VSMC phenotypic switching were examined in vitro, and the protective effects of MR antagonists on AVF outcome were evaluated in a rat AVF model. RESULTS:Dysfunctional fistula exhibited significant medial fibrosis and extracellular matrix deposition, alongside markedly increased MR activity. In the dysfunctional fistula vessels, VSMC displayed reduced expression of the contractile marker SMMHC and features characteristic of a synthetic phenotype, including increased osteopontin expression and heightened proliferation. In vitro studies with cultured VSMC revealed that MR overactivity induced by aldosterone led to phenotypic switching from contractile to synthetic state, concomitant with EGFR-ERK1/2 pathway overactivation. These effects were largely abolished by the MR antagonist finerenone. Knockdown of EGFR expression abrogated ERK1/2 phosphorylation and inhibited the VSMC phenotypic switching. Conversely, ectopic overexpression of EGFR in VSMC diminished the protective effect of finerenone. In rat AVF models, pharmacologic targeting of MR with finerenone significantly improved AVF outcomes, characterized by increased luminal diameters and flow volume, reduced medial fibrosis, and inhibited VSMC phenotypic switching. These beneficial outcomes were likely attributable to a restrained activity of the EGFR-ERK1/2 pathway in VSMC. CONCLUSIONS:Our study demonstrated that therapeutic targeting of MR may improve AVF outcome by modulating VSMC phenotypic switching. These findings offer promising avenues for further clinical investigations aimed at optimizing AVF outcomes in the hemodialysis population.

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Significance Statement Emerging evidence suggests that melanocortin neuropeptides—specifically adrenocorticotropic hormone—offer a novel, steroidogenic-independent therapeutic modality for membranous nephropathy (MN). The molecular mechanism underlying this beneficial effect, however, remains largely elusive. To investigate whether melanocortins modulate humoral immunity, the authors induced passive Heymann nephritis, a model of human MN, in wild-type and melanocortin 1 receptor (MC1R) knockout rats and treated them with melanocortin agents. Additional rats received adoptive transfer of bone marrow-derived cells beforehand from wild-type or MC1R knockout rats. The findings indicate that MC1R signaling plays a key role in negative modulation of B-cell activation and thereby suppresses humoral immune responses in passive Heymann nephritis, and suggest that MC1R signaling might offer a novel B cell–targeted therapeutic strategy for MN. Background Emerging evidence suggests that the pituitary neuropeptide melanocortins—specifically, adrenocorticotropic hormone—offer a novel nonsteroidogenic therapeutic modality for membranous nephropathy (MN). However, the mechanism(s) of action remains elusive. Methods To investigate whether melanocortins modulate humoral immunity, we induced passive Heymann nephritis (PHN), a model of MN, in wild-type (WT) and melanocortin 1 receptor (MC1R) knockout (KO) rats. We treated the animals with melanocortin agents—repository corticotropin injection, the nonsteroidogenic pan-melanocortin receptor agonist [Nle 4 , DPhe 7 ]-α-melanocyte stimulating hormone, the selective MC1R agonist MS05, vehicle gel, or phosphate-buffered saline—and evaluated kidney function, histology, and molecular changes. Additional rats received adoptive transfer of syngeneic bone marrow-derived cells beforehand from WT or MC1R KO rats. Results KO of MC1R worsened PHN and this was associated with increased deposition of autologous immunoglobulin G (IgG) and complement C5b-9 in glomeruli and higher circulating levels of autologous IgG—evidence of a sensitized humoral immune response. Melanocortin therapy ameliorated PHN in WT rats, coinciding with reduced glomerular deposition of autologous IgG and C5b -9. The beneficial efficacy of melanocortins was blunted in KO rats but restored by adoptive transfer of syngeneic bone marrow-derived cells derived from WT rats. Mechanistically, MC1R was expressed in B lymphocytes and was negatively associated with B cell activation. MC1R agonism triggered the expression of microphthalmia-associated transcription factor in activated B cells in a cAMP-dependent mode and also repressed the expression of interferon regulatory factor 4 (a lymphoid transcription factor essential for B-cell development and maturation), resulting in suppressed plasma cell differentiation and IgG production. Conclusions MC1R signaling negatively modulates B cell activation and suppresses humoral immune responses in PHN, suggesting that MC1R signaling might offer a novel therapeutic target for MN.

As a leading cause of chronic kidney disease, diabetic kidney disease (DKD) involves insidious but progressive impairments of renal tubules, and is associated with premature renal aging. The underlying pathomechanisms remain elusive. Post hoc analyses of the publicly-available renal transcriptome revealed that TGFβ1 is overexpressed in renal tubulointerstitia in patients with DKD and positively correlated with kidney aging signaling. This finding was validated in kidney biopsy specimens collected from patients with DKD, associated with renal tubular senescence and degenerative changes. In vitro in renal tubular epithelial cells, exposure to a diabetic milieu, stimulated with high ambient glucose and TGFβ1, elicited premature senescence, as evidenced by staining for senescence-associated β-galactosidase activity and increased expression of p16INK4A, and p53. This coincided with Serpin E1 induction, in parallel with increased fibronectin accumulation and reduced expression of the epithelial marker E-cadherin, all indicative of degenerative changes. Reminiscent of the action of typical senolytics, a small molecule inhibitor of Serpin E1 substantially mitigated the pro-senescent and degenerating effects of the diabetic milieu, suggesting an essential role of Serpin E1 in mediating renal tubular senescence upon diabetic insult. Moreover, inhibition of Serpin E1 abolished the diabetic insult-triggered paracrine senescence of renal tubular cells. In consistency, in patients with DKD, renal tubular expression of Serpin E1 was upregulated and positively correlated with tubular senescence and fibrosis in renal tubulointerstitia. Collectively, diabetic insult induces renal tubular degeneration and premature senescence via, at least in part, Serpin E1 signaling.

Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.

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Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

As life expectancy continues to increase, clinicians are challenged by age-related renal impairment that involves podocyte senescence and glomerulosclerosis. There is now compelling evidence that lithium has a potent antiaging activity that ameliorates brain aging and increases longevity in Drosophila and Caenorhabditis elegans. As the major molecular target of lithium action and a multitasking protein kinase recently implicated in a variety of renal diseases, glycogen synthase kinase 3β (GSK3β) is overexpressed and hyperactive with age in glomerular podocytes, correlating with functional and histological signs of kidney aging. Moreover, podocyte-specific ablation of GSK3β substantially attenuated podocyte senescence and glomerular aging in mice. Mechanistically, key mediators of senescence signaling, such as p16INK4A and p53, contain high numbers of GSK3β consensus motifs, physically interact with GSK3β, and act as its putative substrates. In addition, therapeutic targeting of GSK3β by microdose lithium later in life reduced senescence signaling and delayed kidney aging in mice. Furthermore, in psychiatric patients, lithium carbonate therapy inhibited GSK3β activity and mitigated senescence signaling in urinary exfoliated podocytes and was associated with preservation of kidney function. Thus, GSK3β appears to play a key role in podocyte senescence by modulating senescence signaling and may be an actionable senostatic target to delay kidney aging.

Clinical evidence indicates that the melanocortin peptide ACTH is effective in inducing remission of nephrotic glomerulopathies like minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), including those resistant to steroids. This suggests that a steroid-independent melancortinergic mechanism may contribute. However, the type of melanocortin receptor (MCR) that conveys this beneficial effect as well as the underlying mechanisms remain controversial. Burgeoning evidence suggests that MC5R is expressed in glomeruli and may be involved in glomerular pathobiology. This study aims to test the effectiveness of a novel highly selective MC5R agonist (MC5R-A) in puromycin aminonucleoside (PAN) nephrosis. Upon PAN injury, rats developed evident proteinuria on day 5, denoting an established nephrotic glomerulopathy. Following vehicle treatment, proteinuria continued to persist on day 14 with prominent histologic signs of podocytopathy, marked by ultrastructural glomerular lesions, including extensive podocyte foot process effacement. Concomitantly, there was loss of podocyte homeostatic markers, such as synaptopodin and podocin, and de novo expression of the podocyte injury marker desmin. Treatment with MC5R-A attenuated urine protein excretion and mitigated the loss of podocyte marker proteins, resulting in improved podocyte ultrastructural changes. In vitro in cultured podocytes, MC5R-A prevented the PAN-induced disruption of actin cytoskeleton integrity and apoptosis. MC5R-A treatment in PAN-injured podocytes also reinstated inhibitory phosphorylation and thus averted hyperactivity of GSK3β, a convergent point of multiple podocytopathic pathways. Collectively, pharmacologic activation of MC5R by using the highly selective small-molecule agonist is likely a promising therapeutic strategy to improve proteinuria and glomerular injury in protenuric nephropathies.

EditorialThe Janus view: dual roles for hypoxia-inducible factor in renal repair after acute kidney injuryBohan Chen, Andrew S. Brem, and Rujun GongBohan ChenDivision of Nephrology, University of Toledo Medical Center, Toledo, Ohio, Andrew S. BremDivision of Kidney Disease and Hypertension, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, Rhode Island, and Rujun GongDivision of Nephrology, University of Toledo Medical Center, Toledo, OhioPublished Online:21 Jun 2022https://doi.org/10.1152/ajprenal.00130.2022This is the final version - click for previous versionMoreSectionsPDF (330 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Acute kidney injury (AKI) is an important and independent risk factor for the subsequent development of chronic kidney disease (CKD) with the progressive loss of kidney function and renal fibrosis (1). The underlying causes of progressive CKD remain to be fully elucidated but are likely related to incomplete nephron repair following AKI with the transition from AKI to CKD at the molecular, cellular, and histological level. Functional recovery may occur, but often there is underlying histological evidence of progressive fibrosis.Recovery from AKI depends on the restoration of normal renal tissue following injury (Fig. 1). The process, often referred to as adaptive repair, involves proliferation of surviving renal tubular epithelial cells and vascular endothelial cells, repopulation of renal tubules and peritubular capillaries, resolution of acute inflammation, clearance of cellular debris, and regeneration of parenchymal kidney structures. Severe or repetitive AKI may lead to a maladaptive repair, characterized by degeneration of renal tubules, capillary rarefaction, transformation of acute to chronic inflammation, and gradual but progressive accumulation of myofibroblasts and extracellular matrix in the renal interstitium (1). A number of cellular processes and mediators have been implicated in this maladaptive repair, including cell cycle arrest, stress-induced premature senescence and senescence-associated secretory phenotypes, DNA damage response mediators, epigenetic modifications, and profibrogenic secretome. With AKI, the microcirculation in the kidney is compromised. Interstitial edema often develops from leakage of fluid from increased microvascular permeability or back leak of tubular filtrate into the interstitium, resulting in an increase in the diffusion distance for oxygen and other nutrients. An impaired microcirculation together with interstitial edema causes a hypoxic microenvironment in the post-AKI kidney. As a key sensor of hypoxia and a regulator of the cellular hypoxic response, hypoxia-inducible factor (HIF) mediates many of the cellular adaptations to hypoxia, like increased anaerobic glycolysis, resistance to death, and new blood vessel formation (2). The beneficial role of HIF signaling in protecting against AKI or in post-AKI repair has been described recently using HIF-prolyl hydroxylase inhibitors or by genetic targeting of HIF. However, the timeline of the HIF response in the post-AKI kidney is largely unknown, and it is unclear whether the HIF response can modify renal outcomes following AKI. In an article recently published in the American Journal of Physiology-Renal Physiology, Xu et al. (3) demonstrated that HIF has an important constructive role in adaptive repair following an episode of ischemia-reperfusion injury (IRI)-induced AKI and that HIF production is delayed but is sustained in maladaptive renal repair.Figure 1.Divergent roles of hypoxia-inducible factor (HIF)/β-catenin signaling in adaptive renal repair may determine distinct renal outcomes after acute kidney injury (AKI). Adaptive repair after mild AKI is associated with rapid and transient activation of HIF, whereas maladaptive repair following severe AKI is associated with a delayed and sustained HIF response. Activation of HIF in renal tubules, peritubular capillary endothelial cells, or renal interstitial fibroblasts could trigger the β-catenin signaling and, depending on the timing of the HIF response, could subsequently induce either the expression of c-Myc, cyclin D1, and VEGFα, which are proreparative factors involved in the regeneration of renal tubules and peritubular capillaries and post-AKI repair or the expression of Snail1, fibronectin, and collagen, which are profibrotic mediators involved in renal fibrosis and the transition to chronic kidney disease. PAI-1, plasminogen activator inhibitor-1.Download figureDownload PowerPointIn a murine model of unilateral IRI-induced AKI, short-term ischemia for 20 min caused AKI and subsequent robust renal cell proliferation, resulting in adaptive renal repair, marked by complete restoration of serum creatinine levels by day 28 and full recovery of kidney histology. This adaptive repair was associated with rapid activation of HIF-1α in renal tubules and HIF-2α in peritubular capillary endothelial cells. Given the recent finding that Wnt/β-catenin signaling is also involved in post-AKI repair, and the emerging data suggesting the interaction between HIF and Wnt/β-catenin pathways (4, 5), Xu et al. (3) studied the expression of β-catenin and demonstrated that the induction of HIF correlated with the activation of β-catenin signaling in the post-AKI kidney. To determine if a causal relationship exists between HIF signaling and β-catenin signaling in renal cells after injury, they used the hypoxia/reoxygenation injury model in cultured renal proximal tubular epithelial (HK2) cells and vascular endothelial (EA.hy926) cells. Hypoxia/reoxygenation injury-induced HIF-1α expression in HK2 cells and HIF-2α expression in EA.hy926 cells, both of which promoted cellular proliferation and migration and protected against apoptosis. All these observations were consistent with the in vivo findings. Wnt/β-catenin signaling seems to play a critical role in mediating the protective effect of HIF since the beneficial effect of HIF overexpression was blocked by the Wnt inhibitor IWR-1-endo and was mimicked by the β-catenin activator SKL2001 even in HIF-silenced cells. These results are consistent with the observations that HIF-1α and HIF-2α interact with β-catenin and are essential for β-catenin activation as key modulators of the transcriptional activity of β-catenin in cancer cells (4, 5). The study by Xu et al. (3) would be the first to show the HIF regulation of β-catenin signaling in renal cell recovery from injury. Indeed, a number of HIF-triggered proreparative mediators, such as c-Myc, cyclin D1, and VEGFα, are also typical target molecules of β-catenin signaling and are overexpressed in renal tubular epithelial cells and vascular endothelial cells in a β-catenin-dependent mode after hypoxia/reoxygenation injury (3).Another interesting observation made by Xu et al. (3) is that in severe AKI following a long period of ischemia (30 min), there is a significant delay in the HIF response compared with the response in mild IRI-elicited AKI. The molecular mechanism responsible for the inability to trigger a timely HIF induction is unknown, but massive death and loss of renal parenchymal cells following severe AKI may contribute. Despite the delayed initiation, HIF-1α and HIF-2α activation were inappropriately sustained with severe IRI-AKI leading to maladaptive renal repair and that activation remained upregulated 4 wk after injury. In stark contrast, HIF response in the mild AKI group, i.e., adaptive repair group, returned to normal levels well before 4 wk. Considering the aforementioned role of HIF-1α and HIF-2α in regulating β-catenin activity, it is conceivable that the prolonged HIF response during maladaptive repair may cause persistent β-catenin activation. Although an early and transient β-catenin activation is beneficial for post-AKI repair, a sustained β-catenin activation promotes the transition from AKI to CKD (6). Persistent Wnt/β-Catenin activation is evident in renal interstitial fibroblasts during maladaptive renal repair and is required for renal fibroblast activation. Delayed blockade of Wnt/β-catenin signaling mitigates CKD transition after severe IRI-elicited AKI in mice (6). A number of profibrogenic molecules triggered by HIF, such as Snail1, plasminogen activator inhibitor-1, and fibronectin, are also standard targets of β-catenin signaling (7). There appears to be a time-dependent transition in the pattern of HIF activation from renal tubular epithelia and capillary endothelia to renal interstitial fibroblasts during maladaptive renal repair. Further studies are needed to determine if renal fibroblasts are the site of the sustained HIF response following severe IRI-AKI and associated β-catenin induction. If confirmed, the delayed and sustained HIF response might contribute to CKD transition via promoting continuous β-catenin activation.The findings by Xu et al. (3) may have potential clinical and translational implications. First, with the advent of highly selective small-molecule hypoxia-mimicking agents like the HIF-prolyl hydroxylase inhibitors (HIF stabilizers), treatments to enhance HIF activation have become possible. It is conceivable that enhanced HIF induction by HIF-prolyl hydroxylase inhibitors, early following severe AKI, might be helpful to overcome the insufficient and delayed HIF response and thereby improve the renal outcome. Second, the timing of therapeutic targeting of HIF after AKI seems critical. Based on the study by Xu et al. (3), it seems that an early HIF activation by prolyl hydroxylase inhibitors would be ideal. Delayed/prolonged HIF activation may result in persistent β-catenin signaling and the transition to CKD thus should be avoided. Indeed, a number of studies have implicated the detrimental role of HIF in renal fibrosis (8). Also, there have been concerns about the potential profibrotic effects of HIF-prolyl hydroxylase inhibitors on the kidney during post-AKI repair (9).In summary, the work by Xu et al. (3) demonstrates the dual “Janus-like” roles of the HIF response in post-AKI renal repair with contrasting and even opposite pathobiological characteristics. Following mild AKI, an early and transient HIF response occurs and exerts a proreparative beneficial effect, resulting in adaptive renal repair. In contrast, after severe AKI, a delayed and sustained HIF response ensues and plays a profibrotic and detrimental role in maladaptive repair and CKD transition (Fig. 1). Further studies to determine the precise role and timing of HIF therapy after AKI are needed to make these findings relevant for clinical practice.GRANTSR.G. was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK092485 and DK114006.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSR.G. conceived and designed research; B.C. prepared figures; B.C. and R.G. drafted manuscript; A.S.B. and R.G. edited and revised manuscript; B.C., A.S.B., and R.G. approved final version of manuscript.REFERENCES1. Basile DP, Bonventre JV, Mehta R, Nangaku M, Unwin R, Rosner MH, Kellum JA, Ronco C; ADQI XIII Work Group. Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol 27: 687–697, 2016. doi:10.1681/ASN.2015030309. Crossref | PubMed | ISI | Google Scholar2. Liu Z, Dong Z. A cross talk between HIF and NF-κB in AKI. Am J Physiol Renal Physiol 321: F255–F256, 2021. doi:10.1152/ajprenal.00256.2021. Link | ISI | Google Scholar3. Xu ZH, Wang C, He YX, Mao XY, Zhang MZ, Hou YP, Li B. Hypoxia-inducible factor protects against acute kidney injury via the Wnt/β-catenin signaling pathway. Am J Physiol Renal Physiol 322: F611–F624, 2022. doi:10.1152/ajprenal.00023.2022. Link | ISI | Google Scholar4. Luo Y, Li M, Zuo X, Basourakos SP, Zhang J, Zhao J, Han Y, Lin Y, Wang Y, Jiang Y, Lan L. β-Catenin nuclear translocation induced by HIF-1α overexpression leads to the radioresistance of prostate cancer. Int J Oncol 52: 1827–1840, 2018. doi:10.3892/ijo.2018.4368. Crossref | PubMed | ISI | Google Scholar5. Choi H, Chun YS, Kim TY, Park JW. HIF-2α enhances β-catenin/TCF-driven transcription by interacting with beta-catenin. Cancer Res 70: 10101–10111, 2010. doi:10.1158/0008-5472.CAN-10-0505. Crossref | PubMed | ISI | Google Scholar6. Huffstater T, Merryman WD, Gewin LS. Wnt/β-catenin in acute kidney injury and progression to chronic kidney disease. Semin Nephrol 40: 126–137, 2020. doi:10.1016/j.semnephrol.2020.01.004. Crossref | PubMed | ISI | Google Scholar7. Xie S, Su J, Lu A, Lai Y, Mo S, Pu M, Yang T. Soluble (pro)renin receptor promotes the fibrotic response in renal proximal tubule epithelial cells in vitro via the Akt/β-catenin/Snail signaling pathway. Am J Physiol Renal Physiol 319: F941–F953, 2020. doi:10.1152/ajprenal.00197.2020. Link | ISI | Google Scholar8. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117: 3810–3820, 2007. doi:10.1172/JCI30487. Crossref | PubMed | ISI | Google Scholar9. Tanaka S, Tanaka T, Nangaku M. Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol 307: F1187–F1195, 2014. doi:10.1152/ajprenal.00425.2014. Link | ISI | Google ScholarAUTHOR NOTESCorrespondence: R. Gong (Rujun.[email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation CollectionsAJP-Renal CollectionsAcute Kidney Injury Related ArticlesFirst Author Spotlight 13 Jul 2022American Journal of Physiology-Renal PhysiologyCited BySodium–glucose cotransporter inhibitors and kidney fibrosis: review of the current evidence and related mechanisms19 December 2022 | Pharmacological Reports, Vol. 75, No. 1 More from this issue > Volume 323Issue 1July 2022Pages F1-F3 Crossmark Copyright & PermissionsCopyright © 2022 the American Physiological Society.https://doi.org/10.1152/ajprenal.00130.2022PubMed35635325History Received 4 May 2022 Accepted 25 May 2022 Published online 21 June 2022 Published in print 1 July 2022 Keywordsacute kidney injuryhypoxia-inducible factor Metrics

Spinal cord injury (SCI) damages sensory systems, producing chronic neuropathic pain that is resistant to medical treatment. The specific mechanisms underlying SCI‐induced neuropathic pain (SCI‐NP) remain unclear, and protein biomarkers have not yet been integrated into diagnostic screening. To better understand the host molecular pathways involved in SCI‐NP, we used the bioinformatics method, the PubMed database and bioinformatics methods to identify target genes and their associated pathways. We reviewed 2504 articles on the regulation of SCI‐NP and used the text mining of PubMed database abstracts to determine associations among 12 pathways and networks. Based on this method, we identified two central genes in SCI‐NP: interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α). Adult male Sprague–Dawley rats were used to build the SCI‐NP models. The threshold for paw withdrawal was significantly reduced in the SCI group, and TLR4 was activated in microglia after SCI. Enzyme‐linked immunosorbent assay（ELISA) analysis of TNF‐α and IL‐6 levels was significantly higher in the SCI group than in the sham group. Western blot showed that expressions of the TLR4/MyD88/NF‐κB inflammatory pathway protein increased dramatically in the SCI group. Using the TLR4 inhibitor TAK‐242, the pain threshold and expressions of inflammatory factors and proteins of the proteins of the inflammatory signal pathway were reversed, TLR4 in microglia was suppressed, suggesting that SCI‐NP was related to neuroinflammation mediated by the TLR4 signalling pathway. In conclusion, we found that TNF‐α and IL‐6 were the neuroinflammation‐related genes involved in SCI‐NP that can be alleviated by inhibiting the inflammatory pathway upstream of the TLR4/MyD88/NF‐κB inflammatory pathway.