| dc.description.abstract | Chronic kidney disease (CKD) is a significant cause of death in dogs. However,
the gene and microRNA (miRNA) expression profile that affects progression in CKD has
only been partially characterized. Dogs with X-linked hereditary nephropathy (XLHN)
have a glomerular basement membrane defect that leads to progressive juvenile-onset
renal failure, and their disease is analogous to Alport syndrome in humans. Therefore,
dogs with XLHN not only serve as a good model of canine CKD but also an animal model
for Alport syndrome in humans. In the report, kidney tissue mRNA and small RNA
sequencing were used to aid in the characterization of CKD progression in colony dogs
with XLHN. Further, biofluid miRNA expression in serum and urine was characterized to
serve as potential biomarkers in canine patients with natural-occurring glomerular
diseases.
Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE
miRs) were identified via mRNA and small RNA sequencing in serial kidney biopsies
obtained from dogs with XLHN. The DEGs and the top-ranked miRNA target genes
derived from DE miRs were used to identify enriched biological processes, overrepresented
pathways, and upstream regulators that contribute to kidney disease
progression. Differentially expressed genes and DE miRs identified over 3 clinical time
points revealed upregulation of inflammatory pathways, and TGF-b1 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 and DE
miRs can be potential biomarkers and therapeutic targets translatable to all CKDs.
Biofluid miRNA detection was performed in carrier female dogs with XLHN. This
preliminary study helped optimize RNA isolation and library preparation methods for
canine serum and urine. A biofluid miRNA biomarker study was then performed in dogs
with 3 types of glomerular diseases diagnosed histopathologically: focal segmental
glomerulosclerosis, immune complex glomerulonephritis, and amyloidosis. Compared
with healthy control dogs, DE miRs were identified in the serum and urine from dogs with
mild or advanced tubulointerstitial fibrosis in all 3 diseases. Several miRs showed promise
in their ability to distinguish among these 3 glomerular diseases. These results will provide
non-invasive options for diagnosing canine glomerular diseases. | en |
