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.