Circulating Levels of miRNAs in Canines Associated with Impaired Kidney Function

Background: Mature microRNAs (miRNAs) have been implicated in inflammation and fibrosis and are associated with the pathogenesis of renal dysfunction. miRNAs are single-stranded RNAs approximately 22 nucleotides in length that can posttranscriptionally modify mRNA by base-pairing with its complementary sequences leading to the silencing of mRNA. Methods: We assessed circulating levels of miRNAs in the blood of dogs that were clinically diagnosed as having chronic kidney disease (CKD) post-mortem, after the dogs had lived their full lives. Gene expression was measured using a Canine miRNA PCR array from blood samples that were collected at the natural end-of-life necropsy from dogs with CKD (2-17 yr) and control dogs (5-13.5 yr). Results: End-of-life pathology reports indicated interstitial inflammation, fibrosis, and thickening of the Bowman's capsule. Histopathological analysis of H&E-stained renal sections taken from end-of-life samples showed a significantly higher number of healthy glomeruli as assessed morphologically in controls compared with CKD. There was a significant decline in the levels of miRNAs cfa-let-7a, cfa-let-7c, cfa-let-7f, and cfa-let-7g in dogs with CKD compared with controls. In addition, there was also a ≥1.5-fold reduction in levels of cfa-miR-93, cfa-miR-122, cfa-miR-200a, and cfa-miR-204 in CKD compared with controls (all ns). These microRNAs may have potential anti-fibrogenesis effect and are also down-regulated in rodent models and in in vitro mechanistic models of renal fibrosis, leading to increased fibrosis. There was also a down-regulation of cfa-miR-16 (-2.76 fold, ns), which is consistent with its reported role in attenuating kidney injury independent of fibrosis. Conclusions: Down-regulation of these miRNAs may be indicative of a reduction in their role in attenuating renal function, leading to impaired kidney function and possibly fibrogenesis. Importantly, the circulating miRNAs may serve as non-invasive biomarkers for impaired renal function in CKD. Nutritional interventions that upregulate selected miRNAs may serve as important targets for slowing the progression of CKD.