Project Summary
The rise in an aging population plagued by obesity and diabetes mellitus is projected to render exponential
growth in diabetic kidney disease (DKD). Hence, therapeutic interventions that halt aging-related kidney changes
and DKD must be rigorously pursued. Maladaptive inflammation drives DKD onset, and proinflammatory
cytokines and chemokines activate macrophages leading to kidney infiltration and poor renal prognosis. Yet,
inflammation remains a major unaddressed injurious pathway in DKD. We and others demonstrated that
maladaptive inflammation in DKD patients and animal models is associated with increased cellular senescence
and kidney dysfunction. Thus, decreasing senescence through senotherapeutics, such as, small molecule drugs
or cell-derived components, may halt DKD and age-related kidney deterioration. Therefore, there is an urgent
need to develop a therapeutic armamentarium targeting the multifaceted pathogenesis (inflammation and cell
senescence) of DKD to extend healthy lifespan. We and others demonstrated that mesenchymal stromal cells
(MSCs) suppress inflammatory responses through secretion of extracellular vesicles (EVs) containing
biologically active cargo, primarily microRNAs (miRNAs), and reduce senescent burden and extend lifespan in
aging mouse models. Although the therapeutic activity of MSC-EVs has previously been assessed in aging and
inflammatory disease models, the effects of these biotherapeutics on inflammation and senescence in aging
DKD remain unexplored. Our preliminary results indicate that MSC-EVs: (i) reduce senescence pathways,
macrophage infiltration, and kidney injury in murine DKD and (ii) can be loaded with small molecule drugs for
combination therapy. Additionally, our recent study demonstrated, for the first time, that senolytic drugs, dasatinib
and quercetin, reduce senescent cell abundance in humans and improve kidney injury following senescent cell
clearance in mouse models. We hypothesize that EVs have anti-inflammatory and senotherapeutic effects in
aging DKD, that can be further enhanced by co-delivery of senolytic drugs. To address this central hypothesis,
we will determine the effects of EV miRNAs on senescence and inflammation in vitro (Aim 1), assess the effects
of EVs from several sources in a mouse model of aging DKD (Aim 2), and evaluate the performance of EVs as
drug delivery vehicles for dasatinib and quercetin (Aim 3). To ensure the technical success of this study, we
have assembled a team with complementary expertise in aging, DKD, extracellular vesicles, senolytics, and drug
delivery. Novel approaches encompassing unique EV sources, EV isolation methods, and immunoprofiling
technology will enhance knowledge of EV-mediated therapeutic mechanisms in DKD and may advance clinical
translation of EVs as novel senotherapeutics, delivery vehicles for senolytics, and/or combination therapies to
reduce inflammatory and senescence pathways in diabetic and age-related kidney dysfunction. These novel
therapeutics hold potential to alter disease trajectory and extend the healthy lifespan in those with aging DKD.