Integrin-linked kinase mediates the hydrogen peroxide-dependent transforming growth factor-β1 up-regulation

González-Ramos, Marta; Garcı́a, Soledad; Griera, Mercedes; Luengo, Alicia; Olmos, Gemma; Rodríguez‐Puyol, Diego; Calleros, Laura; Rodrı́guez-Puyol, Manuel

doi:10.1016/j.freeradbiomed.2013.04.029

Cited by 21 publications

(20 citation statements)

References 61 publications

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“…Every injury was the same ODQ concentration (1 μmol/L) prior to the CIS treatment. We previously published that ILK depletion in cultured HMC by specific siRNAs significantly reduces the levels of ILK (28) and also that cGMP-related proteins are upregulated when ILK is modulated (23). Figure 10 confirms that ILK-depletion in vitro upregulates sGC and PKG in HMC ( Figure 1A) and mIMCD3 ( Figure 10D).…”

Section: Ilk Depletion Improves Emt and Inflammation Events In Cis-insupporting

confidence: 58%

“…ILK is thus crucial in several processes and diseases, ranging from fibrosis to cancer (26). Our previous works, in conjunction with other authors, involved ILK or downstream effectors in inflammatory responses, EMT and fibrosis during renal damage (2,5,(27)(28)(29)(30)(31)(32)(33)(34)(35). However the role of ILK during AKI remains elusive.…”

Section: In Vivo Experimentsmentioning

confidence: 97%

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Renal Integrin-Linked Kinase Depletion Induces Kidney cGMP-Axis Upregulation: Consequences on Basal and Acutely Damaged Renal Function

Cano-Peñalver

Griera

García-Jérez

et al. 2015

Mol Med

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Soluble guanylyl cyclase (sGC) is activated by nitric oxide (NO) and produces cGMP, which activates cGMP-dependent protein kinases (PKG) and is hydrolyzed by specific phosphodiesterases (PDE). The vasodilatory and cytoprotective capacity of cGMP-axis activation results in a therapeutic strategy for several pathologies. Integrin-linked kinase (ILK), a major scaffold protein between the extracellular matrix and intracellular signaling pathways, may modulate the expression and functionality of the cGMP-axis-related proteins. We introduce ILK as a novel modulator in renal homeostasis as well as a potential target for cisplatin (CIS)-induced acute kidney injury (AKI) improvement. We used an adult mice model of depletion of ILK (cKD-ILK), which showed basal increase of sGC and PKG expressions and activities in renal cortex when compared with wildtype (WT) littermates. Twenty-four h activation of sGC activation with NO enhanced the filtration rate in cKD-ILK. During AKI, cKD-ILK maintained the cGMP-axis upregulation with consequent filtration rates enhancement and ameliorated CIS-dependent tubular epithelial-to-mesenchymal transition and inflammation and markers. To emphasize the role of cGMP-axis upregulation due to ILK depletion, we modulated the cGMP axis under AKI in vivo and in renal cultured cells. A suboptimal dose of the PDE inhibitor ZAP enhanced the beneficial effects of the ILK depletion in AKI mice. On the other hand, CIS increased contractility-related events in cultured glomerular mesangial cells and necrosis rates in cultured tubular cells; ILK depletion protected the cells while sGC blockade with ODQ fully recovered the damage.

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Section: Ilk Depletion Improves Emt and Inflammation Events In Cis-insupporting

confidence: 58%

Section: In Vivo Experimentsmentioning

confidence: 97%

Renal Integrin-Linked Kinase Depletion Induces Kidney cGMP-Axis Upregulation: Consequences on Basal and Acutely Damaged Renal Function

Cano-Peñalver

Griera

García-Jérez

et al. 2015

Mol Med

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“…In addition, we rejected the possibility that these observed ROS increases were the causes of ILK activity upregulation, as we previously described in H 2 O 2 ‐stimulated human mesangial cells (Gonzalez‐Ramos et al . ), as preincubation of cells with N ‐acetylcysteine, an antioxidant that reduces ROS production, did not modify increases in ILK activity induced by uraemic toxins (data not shown).…”

Section: Discussionmentioning

confidence: 87%

“…Cell proteins (30–40 μg) were run in an 8–10% SDS–polyacrylamide gel, transferred onto a nitrocellulose membrane (Trans‐Blot Transfer Medium, Bio‐Rad, CA, USA) and incubated overnight at 4°C with specific antibodies as previously described (Gonzalez‐Ramos et al . ). This incubation was followed by a second incubation with a peroxidase‐conjugated secondary antibody and immunoreactive products were detected by chemiluminescence using the enhanced chemiluminescent Western blotting detection reagents (Amersham Biosciences, Amersham, UK) following the protocol provided by the manufacturer.…”

Section: Methodsmentioning

confidence: 97%

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

García-Jérez

Luengo

Carracedo

et al. 2014

The Journal of Physiology

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Key pointsr Patients with chronic kidney disease have a higher risk of developing cardiovascular diseases than the general population. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which have poor clearance by conventional dialysis.r Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity and in this study we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia.r For the first time, we demonstrate the implication of ILK in the protection against endothelial cell damage (inhibition of proliferation, toxicity, oxidative stress and programed cell death) induced by uraemic serum from chronic kidney disease patients and uraemic toxins.r This molecular mechanism may have clinical relevance because it highlights the importance of maintaining high levels of ILK activity to help preserve endothelial integrity, at least in early stages of chronic kidney disease.Abstract Patients with chronic kidney disease (CKD) have a higher risk of developing cardiovascular diseases. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which, mostly protein-bound compounds such as indoxyl sulfate (IS) and p-cresyl sulphate, having poor clearance by conventional dialysis, induce endothelial toxicity. However, the molecular mechanism by which uraemic toxins regulate early stages of endothelial dysfunction remains unclear. Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity. In this study, we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia. First, we show that incubation of EA.hy926 cells with human uraemic serum from CKD patients upregulates ILK activity. This ILK activation also occurs when the cells are exposed to IS (25-100 μg ml −1 ), p-cresol (10-100 μg ml −1 ) or both combined, compared to human serum control. Next, we observed that high doses of both toxins together induce a slight decrease in cell proliferation and increase apoptosis and reactive oxygen species production. Interestingly, these toxic effects displayed a strong increase when the ILK protein is knocked down by small interfering RNA, even at low doses of uraemic toxins. Abrogation of AKT has demonstrated the ILK/AKT signalling pathway involved in these processes. This study has demonstrated the implication of ILK in the protection against endothelial cell damage induced by uraemic toxins, a molecular mechanism that could play a protective role in the early stages of endothelial dysfunction observed in uraemic patients.

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“…As part of the multiprotein transmembrane complex, integrin-linked kinase (ILK) is a widely expressed scaffold protein that is crucial in several processes and diseases, from fibrosis to cancer (23,24). ILK modulates the activity of different transcription factors by affecting some of the above-mentioned kinases that may regulate AQP2 (25)(26)(27)(28)(29)(30). It also promotes changes in cytoskeletal functions, facilitating the caveolar trafficking of the vesicles to the cell surface (31).…”

mentioning

confidence: 99%

Integrin‐linked kinase regulates tubular aquaporin‐2 content and intracellular location: a link between the extracellular matrix and water reabsorption

Cano-Peñalver

Griera

Serrano³

et al. 2014

FASEB j.

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One of the clinical alterations observed in chronic renal disease (CRD) is the impaired urine concentration, known as diabetes insipidus (DI). Tubulointerstitial fibrosis of the kidney is also a pathological finding observed in CRD and involves composition of extracellular matrix (ECM). However, an association between these two events has not been elucidated. In this study, we showed that the extracellular-to-intracellular scaffold protein integrin-linked kinase (ILK) regulates expression of tubular water channel aquaporin-2 (AQP2) and its apical membrane presence in the renal tubule. Basally, polyuria and decreased urine osmolality were present in ILK conditional-knockdown (cKD-ILK) adult mice compared with nondepleted ILK littermates. No changes were observed in arginine-vasopressin (AVP) blood levels, renal receptor (V2R), or AQP3 expression. However, tubular AQP2 was decreased in expression and apical membrane presence in cKD-ILK mice, where the canonical V2R/cAMP axis activation is still functional, but independent of the absence of ILK. Thus, cKD-ILK constitutes a nephrogenic diabetes insipidus (NDI) model. AQP2 and ILK colocalize in cultured inner medullary collecting duct (mIMCD3) cells. Specific ILK siRNAs and collagen I (Col) decrease ILK and AQP2 levels and AQP2 presence on the membrane of tubular mIMCD3 cells, which impairs the capacity of the cells to transport water under hypotonic stress. The present work points to ILK as a therapeutic target in NDI.

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Integrin-linked kinase mediates the hydrogen peroxide-dependent transforming growth factor-β1 up-regulation

Cited by 21 publications

References 61 publications

Renal Integrin-Linked Kinase Depletion Induces Kidney cGMP-Axis Upregulation: Consequences on Basal and Acutely Damaged Renal Function

Renal Integrin-Linked Kinase Depletion Induces Kidney cGMP-Axis Upregulation: Consequences on Basal and Acutely Damaged Renal Function

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

Integrin‐linked kinase regulates tubular aquaporin‐2 content and intracellular location: a link between the extracellular matrix and water reabsorption

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