Cyclosporine A (CsA) is an immunosuppressive drug that is widely used after organ transplantation and in the treatment of autoimmune diseases. However, CsA-treatment produces a secondary hypertension that contributes to the morbidity and mortality of organ transplant patients. CsA-induced hypertension is mediated by afferent renal nerves (ARN), but the central neural circuitry mediating CsA-induced hypertension is unknown. Here, the neural circuitry that is activated by CsA-induced hypertension will be determined. My overall hypothesis is that CsA activates renal chemoreceptors.
Aim I. Determine the neural pathways activated by CsA. Activated neurons will be identified by immunocytochemical staining for the phosphorylated form of cyclic AMP response element binding protein (pCREB). The advantage that pCREB has over fos staining is that pCREB staining is found in activated first-order neurons.
Aim I 1. Determine whether renal afferent pathways are organized topographically within the dorsal horn. To address this aim, the location of pCREB-stained neurons will be serially reconstructed after CsA, mechano- or chemoreceptor activation and ureteral ligation.
Aim III. Determine the neurotransmitters used by first-order sensory neurons activated by CsA, mechano- or chemoreceptor activation and ureteral ligation by double staining immunocytochemistry. It is predicted that the activated dorsal horn neurons are differentially distributed within the spinal cord and that distinct neurotransmitters are used by the specific functional types of renal afferents. The overall hypothesis will be evaluated by comparing the distribution of pCREB-stained neurons within the spinal segment and by comparing the neurotransmitter phenotype of pCREB-labeled first-order neurons after CsA, mechano- or chemoreceptor activation and uretral ligation. Our understanding of renal afferent pathways and the neural circuitry that is associated with CsA-induced hypertension is limited; a better understanding of these pathways will permit targeted interventions in the future.
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