NMDANOARF · Role of NMDA receptors on experimental renal failure. Relationship with NO

Final Activity Report Summary - NMDANOARF (Role of NMDA receptors on experimental renal failure. Relationship with NO)

The kidney is particularly vulnerable to the effect of many toxic drugs due to its rich blood supply and its ability to concentrate toxins within the medullary interstitium and renal epithelial cells. In addition, the kidney is also an important site for xenobiotic metabolism and may transform relatively harmless parent compounds into toxic metabolites. Furthermore, the dependence of proximal tubular cells on aerobic metabolism makes the kidney very sensitive to relatively short periods of ischemia, observed for instance in heart attack, aortic surgery, etc. Both ischemic and toxic acute renal failure (ARF) are characterised by a reduction in renal blood flow (RBF). The mediators of reduced RBF in ARF remain controversial, especially if the different pathogenic factors on which the experimental model is based and the stage are considered. Chronic renal failure (CRF), in contrast to ARF, is an irreversible disease which leads to the need of substitutive renal function (dialysis) or renal transplantation. The causes of CRF are multiple, and it usually comes as a complication of other pathologies, like for instance diabetes. Like in the case of ARF, nitric oxide (NO) has also been implicated on the pathogenesis of CRF. We tried to determine the involvement, if any, of the NMDA receptors on the kidney pathology. Those receptors are widely expressed on the CNS, but we recently demonstrated that these receptors are also expressed on renal proximal tubular cells. We have demonstrated that NMDAR1, 2a, 2b, and 2d subunits are expressed on those cells. We also demonstrated that the receptor is functional and that, after activation, raises intracellular calcium levels. No relationship has been found with nitric oxide production. We have also demonstrated that in ischemic ARF, the activation of the receptors does not modify the outcome. In contrast, the inhibition of the receptors worsens the condition. Fibrosis is pathological scarring that can lead to organ failure and eventual death. Although it is not known what triggers the fibrotic response, kidney fibrosis is characterised by the presence of myofibroblasts, which are cells that produce scar tissue, and also matrix and matrix-remodeling genes. Those cells are derived from epiythelial cells through the process called Epithelial Mesenchimal Transition. We have also involved the NMDA receptors in the process of EMT. Activation of NMDA receptors leads to a decrease on the EMT induced by TGF beta, suggesting a possible role of NMDA receptors protecting the kidney tissue from the fibrotic response associated with CRF.

Data: CORDIS, © European Union