title: Renal Integrin-Linked Kinase Depletion Induces Kidney cGMP-Axis Upregulation: Consequences on Basal and Acutely Damaged Renal Function.
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 AKIin vivoand 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.
authors.affiliation: Department of Systems Biology, Physiology Unit, Universidad de Alcalà, Alcalà de Henares, Madrid, Spain.|Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Cano-Peñalver
authors.affiliation: Department of Systems Biology, Physiology Unit, Universidad de Alcalà, Alcalà de Henares, Madrid, Spain.|Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera
authors.affiliation: Department of Systems Biology, Physiology Unit, Universidad de Alcalà, Alcalà de Henares, Madrid, Spain.|Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: García-Jerez
authors.affiliation: Department of Systems Biology, Physiology Unit, Universidad de Alcalà, Alcalà de Henares, Madrid, Spain.|Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Marco
authors.initials: M
authors.lastname: Hatem-Vaquero
authors.affiliation: Department of Systems Biology, Physiology Unit, Universidad de Alcalà, Alcalà de Henares, Madrid, Spain.|Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: María Piedad
authors.initials: MP
authors.lastname: Ruiz-Torres
authors.affiliation: Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.|Biomedical Research Foundation and Nephrology Department, Hospital Príncipe de Asturias, Alcalà de Henares, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodríguez-Puyol
authors.affiliation: Department of Systems Biology, Physiology Unit, Universidad de Alcalà, Alcalà de Henares, Madrid, Spain.|Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sergio de
authors.initials: S
authors.lastname: Frutos
authors.affiliation: Department of Systems Biology, Physiology Unit, Universidad de Alcalà, Alcalà de Henares, Madrid, Spain.|Instituto Reina Sofia de Investigaciόn Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Puyol