PSXI-2 - Circulating Mirnas as Non-invasive Biomarkers of Chronic Kidney Disease and Calcium Oxalate Uroliths in Felines

Abstract: Chronic kidney disease (CKD), characterized by progressive loss of kidney function, is a major cause of mortality in cats. Another complication is the formation of calcium oxalate (CaOx) uroliths in the bladder and kidneys of cats, where inflammation has a role in its pathogenesis. MicroRNAs (miRNAs) are small non-coding RNAs which bind to the target mRNA to reduce its function. Depending on the target mRNA, they regulate transcription of several pro-inflammatory genes. We assessed the expression profiles of circulating miRNAs in blood, collected at the natural end-of-life in colony cats, in a retrospective study, in healthy (n=10; 5.9-16 yr), CaOx (n=10, 8.6-13.4 yr), and CKD (n=10; 8.3-15.4 yr). Circulating concentrations of creatinine, symmetric dimethylarginine, and blood urea nitrogen were significantly greater in CaOx and CKD cats compared with controls, indicating kidney dysfunction. Expression of miRNAs, measured by qRT-PCR, was analyzed using the ΔΔCt method and normalized to U6. There was a significant upregulation of miR-155 in CaOx stone formers compared with controls (p < 0.05). miR-155 is increased in the serum and urine of human patients with nephrolithiasis. miR-155 can also promote oxalate-induced renal oxidative stress by suppressing MGP expression. In humans, miR-155 concentrations are negatively correlated with cytokines including IL-1β, IL-6, and TNF-α, suggesting the involvement of inflammation in nephrolithiasis. However, miR-155 was downregulated in CKD compared with controls. miR-16 was also downregulated in CKD cats. Consistent with this, there is downregulation of both the miRNAs in human patients with Stage 4 CKD. Further, miRNAs downregulated in CaOx, but not in CKD, included miR-17, miR-19b, miR-27a, and miR-27b, whereas let-7a, miR-15a, miR-16, miR-29b, and miR-200a were downregulated only in CKD cats. Taken together, the profile of circulating miRNAs in CaOx and CKD cats may serve as important biomarkers in the initiation and progression of renal dysfunction in cats.