Abstract
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.
Highlights
Despite breakthroughs in basic research and medical care, the therapeutic approaches to acute kidney injury (AKI) are unsatisfactory
During AKI, there is an increase of proinflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor β (TGF-β), which promotes the progression of tubular epithelial-to-mesenchymal transition (EMT) [1,2,3]
The differences between the groups were amplified (Figure 1C). Considering this IBMX-dependent Cyclic GMP (cGMP)-marked difference between the groups, we studied the specificity of the Soluble guanylyl cyclase (sGC)-based cGMP production by cotreating more cortical tissue with IBMX and the sGC inhibitor ODQ for 30 min
Summary
Despite breakthroughs in basic research and medical care, the therapeutic approaches to acute kidney injury (AKI) are unsatisfactory. The pathogenesis of AKI involves changes in the oxygenation of renal structures as a consequence of vascular dysfunction and direct cellular damage induced by exogenous toxins, lipoproteins or local mediators. Nephrotoxicity occurs at both the glomerular and tubular levels [1,2,3] and involves multiple mechanisms, including tubular apoptosis and cell death, inflammation, oxidative stress and hypoxia. During AKI, there is an increase of proinflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor β (TGF-β), which promotes the progression of tubular epithelial-to-mesenchymal transition (EMT) [1,2,3]. The final con sequence of AKI is impaired glomerular and tubular function [6,7,8]
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