Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p

Abstract

Aim Renal fibrosis (RF) is a common clinical condition leading to irreversible renal function loss. Tyrosine kinase proteins and microRNAs (miRs) are associated with pathogenesis and we aim to investigate the role of Fer and its partner miR(s) in RF. Method In silico reproduction of Mouse Kidney FibrOmics browser was performed to identify potential miR(s) and target gene(s). In vivo validation was performed in C57BL/6 mice with unilateral ureteral obstruction (UUO). In vitro validation was performed in rat kidney fibroblast NRK-49F cells. Mimics and inhibitors of miR-29c-3p were constructed. The target gene Fer was monitored by RT-PCR and western blotting. The levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in serum and media were measured by ELISA. Results The Fer expression and protein level were gradually increased during 14 days of UUO modeling. miR-29c-3p expression was strongly correlated with that of Fer. In vivo validation showed increased expressions of fibrosis-associated genes and increased phospoho-Smad3 level in the UUO model. Fer-knockdown (KD) significantly decreased expressions of fibrosis-associated genes. Pharmaceutical inhibition of Fer showed similar effects to miR-29c-3p, and miR inhibition showed a significant decrease of excretion of inflammatory factors. Conclusion Dysregulation of miR-29c-3p and Fer plays a role in RF. Pharmaceutical or genetic inhibition of Fer may serve as the potential treatment for RF.

A Proof-of-Concept Analysis of Plasma-Derived Exosomal microRNAs in Interstitial Pulmonary Fibrosis Secondary to Antisynthetase Syndrome

“…Interestingly, miR-29c is upregulated in experimental models of sepsis [ 15 ] and ulcerative colitis [ 16 ], thus confirming its proinflammatory activity. Moreover, miR-29c seems to also display an antifibrotic action [ 17 ] through different mechanisms, such as the modulation of the Fer expression [ 18 ], and the blockade of the macrophage migration inhibitory factor [ 19 ]. Both the proinflammatory and the antifibrotic action of this miRNA might justify its upregulation in ASSD-ILD in the context of a high inflammatory response, and intense B cell activation, possibly associated with an attempt to limit the fibrotic evolution of the disease, but future, further mechanistic studies will be necessary to address its real biological significance.…”