| dc.description.abstract | Chronic kidney disease (CKD) is a common cause of morbidity and mortality in dogs that, by the time diagnosis occurs using traditional biomarkers, significant damage to the kidneys has occurred. Therefore, establishment of biomarkers for detecting kidney disease sooner and monitoring progression of disease is imperative for earlier therapeutic intervention. Glomerular cells engage in multidirectional signaling to maintain homeostasis. Alterations of these signaling pathways lead to disease development, including CKD. Additionally, a change in normal cellular pathways often causes aberrant expression of signaling molecules, which can be measured and used as biomarkers. The primary goal of this research was to evaluate kidney and urine samples from both affected dogs with CKD caused by X-linked hereditary nephropathy (XLHN) and unaffected, age-matched littermates at defined milestones of disease progression to identify variations in cellular molecules for use as potential biomarkers of CKD. Multiple experimental modalities including immunofluorescence, enzyme-linked immunosorbent assays, next generation sequencing, quantitative real-time PCR, and in situ hybridization were employed. First, we were able to establish that the early disease-initiating events demonstrated in Alport mice, namely, mesangial cell filopodia invasion into the GBM leading to aberrant deposition of laminin 211, are likely playing a role in disease initiation in XLHN dogs. We also identified alterations in endothelin-1 levels in both kidney tissue and urine of affected dogs. Furthermore, we found that let-7e, miR-21, miR-142, miR-378, miR-486, and miR-8890 are promising urinary biomarkers for either early detection of CKD and/or for use to monitor disease development. Last, we concluded that miR-21 expression increases in kidney tissue during disease progression, particularly in the renal tubules, and may result in the dysregulation of multiple cellular pathways, contributing to disease pathogenesis In conclusion, understanding the mechanisms of cellular crosstalk and how they relate to pathogenesis of CKD development and progression allows for the identification of detectable factors in the early stages of disease, which can lead to development of both better diagnostic makers and novel therapeutic targets. Given the complexity of CKD, a focused panel of biomarkers would be extremely rewarding. This would provide clinicians with crucial information for earlier diagnosis, evaluating prognosis, and establishing an individualized treatment plan for patients with CKD, thus improving the overall quality of life. | |
