Renal integrin-linked kinase depletion induces kidney cGMP axis upregulation: Consequences on basal and acutely damaged renal function.

Autores: Cano-Peñalver JL, Griera M, García-Jerez A, Hatem-Vaquero M, Ruiz-Torres MP, Rodríguez-Puyol D, De Frutos S, Rodríguez-Puyol M.

Mol Med. 2015 Oct 10. doi: 10.2119/molmed.2015.00059. [Epub ahead of print]

LINK: http://static.smallworldlabs.com/molmedcommunity/content/pdfstore/15_059_Cano-Penalver.pdf

Abstract:

Soluble guanylyl cyclase (sGC) is activated by nitric oxide (NO) and produces cGMP, which activates cGMP-dependent protein kinases (PKG) and is hydrolysed by specific phosphodiesterases (PDE). The vasodilatory and cytoprotective capacity of cGMP-axis activation results in a therapeutical strategy for several pathologies. Integrin-linked kinase (ILK), a major scaffold protein between the extracellular matrix and intracellular signalling pathways, may modulate the expression and functionality of the cGMP axis-related proteins. We introduce ILK as a novel modulator in the 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. 24 hours 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 Zaprinast 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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