Diabetic kidney disease (DKD) is a major debilitating complication of diabetes and a significant healthcare
problem. Current therapies for DKD are not fully efficacious, with many patients still progressing to renal failure.
Inadequate understanding of mechanisms involved in DKD has restricted the development of effective therapies,
which underscores the critical need to identify novel mediators and mechanisms leading to DKD. In the previous
funding period, we made a significant impact by demonstrating the involvement of non-coding RNAs (ncRNAs),
including microRNAs (miRNAs) and long ncRNAs (lncRNAs), in the pathogenesis of DKD. We characterized a
novel lncRNA, lncMGC, in mesangial cells, which is a host transcript of a mega cluster of miRNAs, the miR-379
cluster. We found that lncMGC modulates critical factors associated with DKD and that a GapmeR antisense
oligonucleotide targeting lncMGC ameliorates pathological features of early DKD. However, the molecular and
epigenetic mechanisms by which lncMGC promotes features of DKD, the effects of lncMGC, or miR-379
deficiency in vivo on diabetes/obesity-induced renal dysfunction in mice, and sex-specific effects are unclear.
The current renewal will address these crucial gaps in knowledge using innovative technologies and mice.
The objective of this proposal is to characterize the role of downstream targets and epigenetic regulators of the
IncMGC-miR-379 axis in processes that lead to renal dysfunction and DKD. Extensive new preliminary data
supporting our research goals include identification of: a) key protein binding partners of lncMGC associated with
chromatin remodeling; b) new targets of miR-379 related to DKD pathology; and c) development highly
innovative mouse models by CRISPR-Cas9 editing. We hypothesize that diabetes re-programs the mesangial
cell (MC) transcriptome and epigenome to dysregulate lncMGC, hosted miR-379, and their key target genes that
affect mitochondrial function, oxidative and ER stress resulting in fibrosis, renal dysfunction, and DKD.
Specific Aim 1 will use state-of-the-art Omics profiling and technologies in MCs to determine novel protein targets
and epigenetic mechanisms by which the lncMGC-miR-379 axis promotes DKD. Specific Aim 2 will use novel
mouse models of miR-379 and lncMGC deficiency to evaluate the in vivo roles of lncMGC, miR-379, and related
critical targets in DKD. Specific Aim 3 will utilize a novel humanized lncMGC mouse and GapmeR targeting
human lncMGC to evaluate the translational potential for human DKD treatment.
Because ncRNAs have essential roles in disease states, these continuing studies are both scientifically and
clinically significant for DKD research. The project is innovative because it uses cutting edge technologies, novel
mouse models, and translational methods. Together, they can alter existing paradigms and have a positive
impact by uncovering new ncRNA-mediated regulation of DKD progression, with potentially far-reaching clinical
and therapeutic implications, particularly for patients not responding to currently available treatments.