Inhibiting MicroRNA-503 and MicroRNA-181d with Losartan Ameliorates Diabetic Nephropathy in KKAy Mice

Abstract

BackgroundDiabetic nephropathy (DN) is the most lethal diabetic microvascular complication; it is a major cause of renal failure, and an increasingly globally prominent healthcare problem.Material/MethodsTo identify susceptible microRNAs for the pathogenesis of DN and the targets of losartan treatment, microRNA arrays were employed to survey the glomerular microRNA expression profiles of KKAy mice treated with or without losartan. KKAy mice were assigned to either a losartan-treated group or a non-treatment group, with C57BL/6 mice used as a normal control. Twelve weeks after treatment, glomeruli from the mice were isolated. MicroRNA expression profiles were analyzed using microRNA arrays. Real-time PCR was used to confirm the results.ResultsLosartan treatment improved albuminuria and the pathological lesions of KKAy mice.The expression of 10 microRNAs was higher, and the expression of 12 microRNAs was lower in the glomeruli of the KKAy untreated mice than that of the CL57BL/6 mice. The expression of 4 microRNAs was down-regulated in the glomeruli of the KKAy losartan-treated mice compared to that of the untreated mice. The expression of miRNA-503 and miRNA-181d was apparently higher in the glomeruli of the KKAy untreated mice, and was inhibited by losartan treatment.ConclusionsThe over-expression of miR-503 and miR-181d in glomeruli of KKAy mice may be responsible for the pathogenesis of DN and are potential therapeutic targets for DN.

Interactions Among Non-Coding RNAs in Diabetic Nephropathy

“…Reduction of the E2f3 expression leads to podocyte cells apoptosis and injury, induced by high glucose (Zha et al, 2019). Importantly, in the mice model of DN treated with Losartan (a drug for kidney disease treatment), the prevention of DN progression in those mice was evident with the inhibition of miR-503 action (Zhu et al, 2016), therefore confirming the role of miR-503 in contributing to podocyte cell death. Similarly, miR-181b is also the pro-apoptotic miRNA, and its expression was high in DN patients (Zhu et al, 2019).…”

Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat

“… 36 , 38 On the other hand, a decrease of miRNA-503 upon losartan treatment is associated with an improvement of diabetic nephropathy in an animal model of spontaneous type 2 diabetes. 39 Herein, we report the first evidence that an increase of miR-503 associates with high-salt induced stroke occurrence, through its ability to modulate brain UCP2 expression, in an animal model of spontaneous hypertension and stroke and that, in turn, miR-503 can be decreased by both pharmacological and nutraceutical approaches to obtain protection from stroke. Further studies will address the interaction between PPAR α and miR-503 in the UCP2 regulation.…”

Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin

“…DN has always been recognized as ESRD all over the world, which may be attributed to severe hyperglycemia [30]. Researches already evaluated the various treatments and therapeutic targets, which ameliorating renal fibrosis, including drugs, endocrine hormones, complement systems and miRNAs [8,[31][32][33]. However, these methods have different disadvantages, which hinder the efficacy of the clinical application.…”