MicroRNA-221 Inhibits Latent TGF-?1 Activation through Targeting Thrombospondin-1 to Attenuate Kidney Failure-Induced Cardiac Fibrosis.

ABSTRACT: Kidney failure (KF) is associated with cardiac fibrosis and significantly increased mortality in heart failure. Thrombospondin-1 (TSP1), a key regulator of latent transforming growth factor-?1 (L-TGF-?1) activation, is a predicted target of miR-221. We hypothesized miR-221 attenuates severe KF-associated cardiac fibrosis via targeting of Thbs1 with subsequent inhibition of L-TGF-?1 activation. Rat cardiac fibroblasts (cFB) were isolated and transfected with microRNA-221 (miR-221) mimics or mimic control (miR-221 and MC) with or without exposure to L-TGF-?1. We demonstrate miR-221 downregulates Thbs1 via direct 3' untranslated region (3' UTR) targeting with consequent inhibition of L-TGF-?1 activation in cFB as proven by the significant reduction of myofibroblast activation, collagen secretion, TGF-?1 signaling, TSP1 secretion, and TGF-?1 bioactivity measured by Pai1 promoter reporter. The 5/6 nephrectomy (Nx) model of cardiac fibrosis was used to test the in vivo therapeutic efficacy of miR-221 (i.v. 1 mg/kg ×3). miR-221 significantly inhibited Nx-induced upregulation of TSP1 and p-SMAD3 in the heart at day-7 and reduced cardiac fibrosis (picro-sirius), improved cardiac function (±dP/dt), and improved 8-week survival rate (60% versus 36%; p = 0.038). miR-221 mimic treatment improved survival and reduced cardiac fibrosis in a model of severe KF. miR-221 is a therapeutic target to address cardiac fibrosis originating from renal disease and other causes.

SUBMITTER: Zhou Y 

PROVIDER: S-EPMC7645417 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature