Mechanisms of tissue injury in renal artery stenosis: ischemia and beyond

Abstract

Renal injury distal to an atherosclerotic renovascular obstruction reflects multiple intrinsic factors producing parenchymal tissue injury. Atherosclerotic disease pathways superimposed on renal arterial obstruction may aggravate damage to the kidney and other target organs, and some of the factors activated by renal artery stenosis may in turn accelerate the progression of atherosclerosis. This cross-talk is mediated through amplified activation of renin-angiotensin system, oxidative stress, inflammation, and fibrosis-pathways notoriously involved in renal disease progression. Oxidation of lipids also accelerates the development of fibrosis in the stenotic kidney by amplifying profibrotic mechanisms and disrupting tissue remodeling. The extent to which actual ischemia modulates injury in the stenotic kidney has been controversial, partly because the decrease in renal oxygen consumption usually parallels a decrease in renal blood flow, and because renal vein oxygen pressure in the affected kidney is not decreased. However, recent data using novel methodologies demonstrate that intra-renal oxygenation is heterogeneously affected in different regions of the kidney. Activation of such local injury within the kidney may lead to renal dysfunction and structural injury, and ultimately unfavorable and irreversible renal outcomes. Identification of specific pathways producing progressive renal injury may enable development of targeted interventions to block these pathways and preserve the stenotic kidney.

Figure 1

Interplay of mechanisms by which atherosclerosis might aggravate kidney injury in renal artery stenosis. Angiotensin II and reactive oxygen species (ROS) regulate the expression of thrombospondin (TSP), transforming growth factor (TGF)-β, and tissue inhibitors of matrix metalloproteinases (TIMP), leading to a decrease in matrix metalloproteinases (MMP), accumulation of extra-cellular matrix, and fibrosis. Immune responses and inflammatory mediators such as nuclear factor kappa B (NFκB), monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α, contribute to increase oxidative stress, formation of oxidized LDL (ox-LDL), and fibrosis. ROS also scavenge nitric oxide (NO) to form peroxynitrite (ONOO), thereby inducing endothelial dysfunction and loss of the vasculoprotective effects of NO. Similar mechanisms lead to loss of intra-renal microvessels. Modified with permission from (19).

Figure 2

Tomographic images of the renal microcirculation showing microvascular rarefaction in the stenotic kidney (middle panel) compared to normal pig kidney (left), which was improved in RAS pigs treated with chronic antioxidant supplementation (right). The vessels on the cortex and medulla show interlobar vessels (I), arcuate vessels (arrow), and the branching orders of radial vessels (R) with numerous small vessels (*) in the outer third of the cortex (displayed at 40-μm voxel size). Modified with permission from (24).

Figure 3

The relationship between renal oxygen consumption and renal filtration rate (left) and sodium reabsorption rate (right). A decrease in renal metabolic activity is associated with a decrease in total renal oxygen uptake, constituting a mechanism to balance oxygen supply and demand. Modified with permission from (80).

Figure 4

Arterio-venous oxygen shunting is likely to occur in the kidney, in which a counter-current arrangement allows close proximity of arteries and veins. This might be one of the mechanisms that regulate intra-renal oxygenation. The numbers represent oxygen tension along the nephron (mmHg).