• 2018-07
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • Integrin linked kinase ILK is


    Integrin-linked kinase (ILK) is a key intracellular component of the integrin signaling complex that functions as a scaffold molecule and as a serine/threonine protein kinase that links cell-membrane matrix adhesion receptors (integrins) to Pyocyanin cytoskeleton and to numerous intracellular signaling pathways [[9], [10], [11]]. ILK-downstream effectors include glycogen synthase kinase 3β (GSK-3β), protein kinase B (PKB/AKT) and mitogen-activated protein kinases (MAPKs) [12]. ILK is fundamental in survival, proliferation/apoptosis, differentiation, cell adhesion, migration, invasion and ECM deposition [9,11,13,14]. Upregulation of ILK expression and/or activity has been implicated in the pathogenesis of a wide variety of chronic kidney diseases as a mediator during the nephrotic syndrome [15], proteinuria [16,17], podocyte damage [17,18] and diabetic nephropathy [19,20]. Moreover, other authors point to ILK as a key mediator in renal interstitial fibrogenesis and EMT induced by a range of stimuli, including TGF-β1 [21,22], connective tissue growth factor [23] and high glucose levels [17,19,24]. Recently, we demonstrated that ILK depletion in vivo diminishes the expression of EMT marker α-SMA and the inducer TGF-β1, in renal tubular epithelial cells of a cisplatin-induced acute kidney injury model [25]. The mechanisms followed by ILK to promote EMT includes the related to renal fibrosis, and they are executed by specific EMT-TFs such as Snail and Twist, which downregulate the expression of the epithelial marker E-cadherin [19,21,22,26]. In addition, our group demonstrated that abnormally high levels of collagens that are present in renal fibrosis and ECM protein sequences modulate the ILK activity that increases TGF-β1 expression in smooth muscle cells and glomerular mesangial cells, which finally perpetuates ECM production [[27], [28], [29]]. We demonstrated that ILK plays a key role in the regulation of Angiotensin II-induced or cisplatin-induced renal inflammation [25,30], as suggested in other inflammatory contexts [31,32]. In the present work, we used ILK conditional-knockdown mice (cKD-ILK) [25,30] to evaluate 1) whether ILK could be involved in CKD progression and 2) the consequences of ILK abrogation in an experimental model of progressive CKD. In order to do this study, the animals were subjected to an adenine-rich diet that induced renal damage and resembled the uremic features that are present in human CKD [[33], [34], [35]]. Additionally, 3) we also evaluated the potential role of ILK depletion as a therapeutic procedure to be applied after the disease induction, as a more effective approach in the interventions of human CKD subjects. Our results show that ILK may be critical during CKD pathophysiology and progression and therefore the ILK blockade could be a useful therapeutic strategy against CKD.
    Materials and methods
    Discussion In the present study, we assessed the key role of ILK in the genesis and progression of CKD by performing a mouse experimental model where we transgenically depleted ILK at the beginning as well as during the progression of the disease. Our results demonstrate that ILK expression in renal tissue increases as CKD progresses, and this increased ILK content correlates well with different molecules that are considered markers or pathogenic factors of renal damage. Finally, ILK depletion prevents renal disease progression. The contrasted experimental model chosen is based on the administration of high amounts of adenine in the diet [[33], [34], [35]], because adenine induces gradual and progressive kidney damage that allow us to analyze the consequences of ILK depletion through the progression of the disease. The adenine is absorbed and metabolized into DHOA, an insoluble compound that precipitates in renal tubules, which promotes tubular occlusion and tubular epithelium physical injury. DHOA leads to the formation of intratubular casts, with extensive tubular dilation and secondary inflammation, necrosis, foreign-body granulomas and ultimately, tubule-interstitial fibrosis that consequently produce renal dysfunction, characterized by elevated levels of serum urea nitrogen and creatinine [[33], [34], [35]]. Some characteristics of this model resemble the diseases characterized by increased intratubular renal pressure (urologic diseases, chronic renal damage following acute tubular necrosis with intratubular casts) or intratubular accumulation of toxic metabolites or proteins (myeloma kidney, acute renal damage associated to very increased levels of uric acid), and even to the chronic kidney damage described as Mesoamerican nephropathy, that has been proposed to be due to intratubular crystal depositions linked to sustained and repeated dehydrations [40].