Down‐regulation of Circulating miRNAs in Canines with Chronic Kidney Disease may be Indicative of Renal Fibrosis

Abstract

Mature microRNAs (miRNAs) are single‐stranded RNAs approximately 22 nucleotides in length. They are generated from short hairpin RNAs that are produced by the ribonucleases, Drosha and Dicer. miRNAs act as post‐transcriptional regulators by base‐pairing with complementary sequences to mRNAs, generally leading to the silencing of mRNA through either degradation or less efficient translation of their target mRNAs. Circulating miRNAs may also serve as biomarkers for renal dysfunction. One characteristic of chronic kidney disease (CKD) is renal fibrosis which results in a progressive loss of renal function, subsequently leading to renal failure. Mechanisms underlying renal fibrosis, generally characterized by excessive extracellular matrix synthesis and deposition, are not clear but deregulation of miRNAs has been intricately linked to renal fibrosis. We assessed the circulating levels of miRNAs using Qiagen’s Canine mScript miRNA PCR array, in the blood of dogs that were clinically diagnosed as having CKD, post‐mortem. Further, end‐of‐life pathology reports indicated interstitial inflammation, fibrosis, and thickening of the Bowman’s capsule. Blood samples were collected at necropsy from dogs with CKD (n=10; 2–17 yr) and control dogs (n=10; 5–13.5 yr). There was a significant decline in the levels of miRNAs cfa‐let‐7a, let‐7c, let‐7f, and let‐7g in dogs with CKD when compared to controls (p<0.05). Down‐regulation of certain let‐7 miRNAs (let‐7a, let‐7b) has been associated with experimental models of induction of renal fibrogenesis. There was also a >2‐fold reduction (NS) in levels of cfa‐miR‐93, cfa‐miR‐122, cfa‐miR‐200a, and cfa‐miR‐204, in CKD when compared to controls. These microRNAs have been demonstrated to have anti‐fibrogenesis effect, and are also down‐regulated in rodent models and in vitro mechanistic models of renal fibrosis leading to increased fibrosis. There was also a down‐regulation of cfa‐miR‐16, which is consistent with its reported role in attenuating kidney injury independent of fibrosis. Taken together with the literature, down‐regulation of these miRNAs may be indicative of a reduction in their role in attenuating renal fibrogenesis and injury. Importantly, the circulating miRNAs may serve as non‐invasive biomarkers for renal fibrosis in CKD and also as nutritional targets for slowing the progression of fibrosis in kidney disease.Support or Funding InformationThis study was funded by Hill’s Pet Nutrition, Inc