Mechanisms of Renal Structural Alterations in Combined Hypercholesterolemia and Renal Artery Stenosis

Abstract

Objective-Atherosclerotic renovascular disease (ARVD) aggravates renal scarring more than other causes of renal artery stenosis (RAS), but the underlying pathogenic mechanisms of this potential profibrotic effect remain unclear. We tested the hypothesis that coexistence of atherosclerosis and RAS interferes with renal tissue remodeling. Methods and Results-Single-kidney hemodynamics and function were quantified in vivo with electron-beam computed tomography in 3 groups of pigs (nϭ7 each): normal pigs, pigs 12 weeks after induction of unilateral RAS (RAS group), and pigs with similar-degree RAS fed a 12-week 2% hypercholesterolemic diet (HCϩRAS, simulating early ARVD). Kidneys were studied ex vivo by Western blotting and immunohistochemistry. Renal volume, renal blood flow, and glomerular filtration rate were similarly decreased in RAS and HCϩRAS ischemic kidneys, accompanied by similar increased expression of profibrotic factors like transforming growth factor-␤, tissue inhibitor of metalloproteinase-1, and plasminogen activator inhibitor-1. Nevertheless, HCϩRAS kidneys showed increased intrarenal fibrosis compared with RAS-only kidneys. Furthermore, expression of nuclear factor-B was increased, expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems was decreased, and apoptosis was blunted. Conclusions-Diet-induced HC superimposed on RAS accelerates the development of fibrosis in the stenotic kidney by amplifying profibrotic mechanisms and disrupting tissue remodeling. These alterations might contribute to renal disease progression in ARVD and might account for the increased propensity for end-stage renal disease.

Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia

“…Indeed, we showed previously that diet-induced HC (a surrogate of early atherosclerosis) led to renal functional and structural impairment, likely through activation of redox-sensitive mechanisms (3,4,19) that also involved the activation of the UPS (15,16). Furthermore, we also showed that the UPS is functionally active in early coronary atherogenesis (30).…”

“…We showed previously in both human (29) and animal (15,16,30) studies that activation of the UPS may potentially play a deleterious role in different stages of atherosclerosis.…”

“…In line with these observations, emerging evidence supports the notion that proteasome inhibitors (PSI) may be vasculo-and tissue-protective (11,13). Notably, the UPS may also contribute to renal injury (14), and we recently observed its activation in the early stage of experimental renovascular disease (15,16). However, the potentially beneficial effects of PSI on the kidney in the early stage of atherogenesis, a proinflammatory condition associated with increased NF-B and UPS activation, remain unknown.…”

Paradigm Shifts in Atherosclerotic Renovascular Disease

“…35 These vessels demonstrate disturbances of oxidative pathways, generation of toxic oxygen species, and free radicals that accelerate intrarenal injury and fibrosis. 36 To some degree these pathways can be modified by statin and/or antioxidant therapy in animal models. 37,38 Importantly, prolonged reductions in renal perfusion pressures and flows in these models lead to microvascular rarefication with partial collapse and obliteration of the arteriolar microcirculation.…”

“…Loss of microvessels, particularly in the renal cortex, results from perivascular fibrosis, metabolically driven injury to the vessel walls, and degradation of growth factors by reactive oxygen species. 36 Local oxidative stress associated with mitochondrial dysfunction and apoptosis appears to participate in vessel loss and tubulointerstitial fibrosis. Consistent with these effects in the atherosclerotic environment produced by high-cholesterol feeding, aggressive administration of statins reduces oxidative stress injury in animal models and diminishes tissue TGF-b expression and fibrosis measurably in human nephrectomy samples.…”