Abstract
Dogs with X-linked hereditary nephropathy (XLHN) have a glomerular basement membrane defect that leads to progressive juvenile-onset renal failure. Their disease is analogous to Alport syndrome in humans, and they also serve as a good model of progressive chronic kidney disease (CKD). However, the gene expression profile that affects progression in this disease has only been partially characterized. To help fill this gap, we used RNA sequencing to identify differentially expressed genes (DEGs), over-represented pathways, and upstream regulators that contribute to kidney disease progression. Total RNA from kidney biopsies was isolated at 3 clinical time points from 3 males with rapidly-progressing CKD, 3 males with slowly-progressing CKD, and 2 age-matched controls. We identified 70 DEGs by comparing rapid and slow groups at specific time points. Based on time course analysis, 1,947 DEGs were identified over the 3 time points revealing upregulation of inflammatory pathways: integrin signaling, T cell activation, and chemokine and cytokine signaling pathways. T cell infiltration was verified by immunohistochemistry. TGF-β1 was identified as the primary upstream regulator. These results provide new insights into the underlying molecular mechanisms of disease progression in XLHN, and the identified DEGs can be potential biomarkers and therapeutic targets translatable to all CKDs.
Highlights
Dogs with X-linked hereditary nephropathy (XLHN) have a glomerular basement membrane defect that leads to progressive juvenile-onset renal failure
X-linked hereditary nephropathy (XLHN) in dogs leads to chronic kidney disease (CKD) because of a defect in type IV collagen in the glomerular basement membrane (GBM)
The degree of fibrosis in the rapid group was more severe at T2 and T3 than that in the slow group, despite the two groups being clinically indistinguishable; statistical significance between the scores was reached only at T3 (Supplementary Table S1 and Fig. S1)
Summary
Dogs with X-linked hereditary nephropathy (XLHN) have a glomerular basement membrane defect that leads to progressive juvenile-onset renal failure. Their disease is analogous to Alport syndrome in humans, and they serve as a good model of progressive chronic kidney disease (CKD). TGF-β1 was identified as the primary upstream regulator These results provide new insights into the underlying molecular mechanisms of disease progression in XLHN, and the identified DEGs can be potential biomarkers and therapeutic targets translatable to all CKDs. X-linked hereditary nephropathy (XLHN) in dogs leads to chronic kidney disease (CKD) because of a defect in type IV collagen in the glomerular basement membrane (GBM). Varied times of onset and rates of progression are common among different types of mutations in people with AS6, disease progression may vary among members of an AS family with an identical mutation[7], as seen in dogs[8]
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