Renal injury in atherosclerotic renovascular disease (RVD) often progresses despite restoring large vessel patency. This process is linked to rarefaction of microvessels, cortical hypoxia, stimulation of inflammatory cytokines and recruitment of progenitor and inflammatory cells. Our overall hypothesis is that the severity of renal injury and recovery in human RVD will depend upon not only restoration of blood flow but also a transition from a pro-inflammatory, fibrogenic phenotype to one favorable to restoring tubular integrity that will reflect the functional balance of M1 (inflammatory) and M2 (reparative) macrophages.
The specific aims i n this project apply novel technologies to define cortical and medullary blood flow and oxygenation in human subjects. They will be combined with studies of kidney biopsies and renal venous cytokine patterns that can be ascribed to M1 or M2 macrophages. We propose to modify the inflammatory and angiogenic pathways by delivering intra-renal autologous adipose-derived mesenchymal stem cells (MSCs) capable of immunomodulation.
Specific Aim 1 will define the relationship between cortical and medullary blood flows, tissue hypoxia, and inflammatory signals, defined by trans-renal cytokine gradients in RVD. Our hypothesis is that the level of cortical hypoxia (defined both by blood flow reduction and elevated deoxyhemoglobin) will be related to induction of inflammatory homing signals.
Specific Aim 2 will undertake to modify the intrarenal microenvironment by delivery of autologous adipose-derived MSCs in advanced RVD. The hypothesis to be tested is that MSCs will result in measurable increases in glomerular filtration, cortical and medullary blood flow and oxygenation, and reduced tissue inflammation with a cytokine signature characteristic of M2 macrophages.
Specific Aim 3 will combine administration of MSC's to individuals with advanced RVD undergoing renal revascularization via renal artery stenting. Our hypothesis is that MSCs combined with renal artery stenting will augment tissue repair and will better restore kidney oxygenation and function than MSCs alone. These studies will provide the first investigation in humans of the potential for cell-based therapy to augment vascular and functional repair after restoring blood flow to the kidney.
These studies are relevant to prevention of progressive kidney disease, particularly in older subjects with widespread vascular disease. They will address directly evolving concepts linking large-vessel occlusive disease to inflammatory renal injury. Importantly, these studies will for the first time explore the role of mesenchymal stem cells as a means to repair tissue injury beyond an occlusive vascular lesion in humans.
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