Objective Endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) augment tissue repair, but possess slightly different properties. How the cellular phenotype affects the efficacy of this approach in renovascular disease is incompletely understood. This study tested the hypothesis that EPC and MSC protect the post-stenotic kidney by blunting different disease pathways. Methods Peripheral blood EPC and adipose-derived MSCs were expanded and characterized by cell surface markers (e.g. CD34/KDR, or CD44/CD90). Single-kidney hemodynamics and function were assessed in pigs after 10 weeks of renal artery stenosis (RAS) treated 4 weeks earlier with an intra-renal infusion of vehicle (n=7), EPC (RAS+EPC) or MSC (RAS+MSC) (both 10×10^6, n=6), and normal controls (n=7). Kidney disease mechanisms were evaluated ex-vivo. The ability of EPC and MSC to attenuate endoplasmic reticulum (ER) stress was also studied in isolated ER and in tubular cells co-cultured with EPC and MSC. Results Glomerular filtration rate in RAS was lower than controls, increased in RAS+EPC, and further improved in RAS+MSC, although both improved renal blood flow similarly. EPC prominently enhanced renal growth-factor expression and decreased oxidative-stress, while MSC more significantly attenuated renal inflammation, ER-stress, and apoptosis. Furthermore, MSC induced a greater decrease in caspase-3 and CHOP expression in cultured tubular cells through mechanisms involving cell contact Conclusion EPC and MSC achieve a comparable decrease of kidney injury in RAS by different mechanisms, although MSC elicited slightly superior improvement of renal function. These results support development of cell-based approaches for management of renovascular disease, and suggest cell selection based on the underlying pathophysiology of kidney injury.

Percutaneous transluminal renal stenting (PTRS) does not consistently improve renal function in patients with atherosclerotic renovascular disease, but the mechanisms underlying irreversible kidney injury have not been fully elucidated. We hypothesized that renal dysfunction after PTRS is linked to ongoing renal microvascular (MV) remodeling. Pigs were studied after 10 wk of atherosclerosis and renal artery stenosis (ARAS), ARAS treated with PTRS 4 wk earlier, and normal controls (n = 10 each). Renal blood flow (RBF) and glomerular filtration rate (GFR) were studied using multidetector computer tomography. Renal microvascular architecture (micro-CT), angiogenic activity, oxidative stress, and fibrosis were evaluated ex vivo. Four weeks after PTRS, blood pressure was normalized. However, GFR and RBF remained similarly decreased in untreated ARAS and ARAS+PTRS (P < 0.05 vs. normal). MV rarefaction was unaltered after revascularization, and the spatial density of outer cortical microvessels correlated with residual GFR. Interstitial fibrosis and altered expression of proangiogenic and profibrotic factors persisted after PTRS. Tubulointerstitial injury in ARAS persisted 4 wk after mechanically successful PTRS, and vessel loss correlated with residual renal dysfunction. MV loss and fibrosis in swine ARAS might account for persistent renal dysfunction after PTRS and underscore the need to assess renal parenchymal disease before revascularization.

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Urbieta-Caceres VH, Lavi R, Zhu XY, Crane JA, Textor SC, Lerman A, Lerman LO. Early atherosclerosis aggravates the effect of renal artery stenosis on the swine kidney. Am J Physiol Renal Physiol 299: F135-F140, 2010. First published May 12, 2010 doi:10.1152/ajprenal.00159.2010.-Atherosclerotic renal artery stenosis (ARAS) is increasingly identified in patients with end-stage renal disease. Renal function in ARAS patients deteriorates more frequently than in nonatherosclerotic renal artery stenosis (RAS). This study was designed to test the hypothesis that atherosclerosis modifies the relationship between single-kidney hemodynamics and function and the severity of stenosis. The degree of unilateral RAS in domestic pigs (4 normal, 26 RAS, and 22 ARAS) was correlated with renal function and hemodynamics evaluated by 64-slice multidetector computerized tomography before and after endothelium-dependent challenge with ACh. The degree of stenosis and increase in mean arterial pressure were similar in RAS and ARAS. Stenotic single-kidney volume, blood flow, glomerular filtration rate, and cortical perfusion were lower than normal in both RAS and ARAS, but only in RAS correlated inversely with increasing degree of stenosis (r ϭ Ϫ0.62, r ϭ Ϫ0.49, r ϭ Ϫ0.51, and r ϭ Ϫ0.46, respectively, P Ͻ 0.05 for all). Basal tubular fluid concentration capacity and stenotic cortical perfusion response to ACh were both blunted only in ARAS. This study shows that atherosclerosis modulates the impact of a stenosis in the renal artery on stenotic kidney hemodynamics, function, and tubular dynamics. These observations underscore the direct intrarenal effect of atherogenic factors on the kidneys. renovascular hypertension; multidetector CT ATHEROSCLEROTIC RENAL ARTERY stenosis (ARAS) is a common manifestation of generalized atherosclerosis and is the predominant renal arterial lesion in patients over 50 years old (9). ARAS is present in up to 50% of those with atherosclerotic disease elsewhere (10). Moreover, ARAS is an independent risk factor for aggravation of cardiovascular disease (8) and may lead to renovascular hypertension and ischemic nephropathy.While the severity of parenchymal damage in the ischemic ARAS kidney is an important prognostic factor for renal function (24), the degree of the stenosis does not necessarily predict renal hemodynamics and function distal to renal artery stenosis (RAS) (13,20). It is recognized that high-grade atherosclerotic lesions in the renal artery may decrease renal perfusion and impair renal function. Therefore, therapeutic strategies have focused on restoring renal blood supply. However, improvement in blood pressure control or recovery of renal function after renal revascularization are achieved only in selected ARAS patients (22, 23), whereas repair of renal arterial lesions uncomplicated by atherosclerosis often achieves better outcomes (14). These observations suggest that deleterious factors beyond the stenosis, probably triggered by the atherogenic process, play dominant roles in compromising ...

Aim Atherosclerotic renovascular disease (ARVD) may impair renal function and increase cardiovascular morbidity and mortality, but the mechanism by which ARVD impacts cardiovascular function is unclear. We tested the hypothesis that preservation of renal function can reverse cardiac dysfunction in ARVD. Methods and results Endothelial progenitor cells (EPC) were injected intra-renally (ARVD + EPC) after 6 weeks of swine ARVD (concurrent hypercholesterolemia and renovascular hypertension), and single kidney function and myocardial blood-flow and microvascular permeability (MP) responses to adenosine were assessed using CT 4 weeks later. Myocardial microvascular density was evaluated by micro-CT. Inflammation and oxidative-stress were assessed in kidney venous and systemic blood samples. Normal and untreated ARVD pigs served as controls. Blood pressure was similarly increased in ARVD and ARVD + EPC. Compared to normal, ARVD showed lower glomerular filtration rate, elevated renal vein and systemic oxidized LDL (ox-LDL), aldosterone, uric acid, isoprostanes, transforming growth factor (TGF)-, and interleukine-6. Renal vein ox-LDL and TGF-showed a positive gradient across the stenotic kidney, indicating increased renal oxidative stress and fibrogenic activity. Furthermore, ARVD impaired myocardial blood-flow and MP response to adenosine, decreased microvascular density, and induced myocardial fibrosis. Improvement of renal function in ARVD + EPC decreased systemic aldosterone, inflammation, and oxidative stress, and improved myocardial microvascular integrity and density. Conclusion Selective improvement in renal function, which reduced renal and systemic oxidative stress and inflammation, preserved remote myocardial microvascular function and architecture, despite enduring hypertension. These findings underscore functionally important cardiorenal crosstalk possibly mediated by renal injury signals.

LO. Age-dependent renal cortical microvascular loss in female mice. Am J Physiol Endocrinol Metab 302: E979 -E986, 2012. First published February 7, 2012 doi:10.1152/ajpendo.00411.2011.-Renal function and blood flow decline during aging in association with a decrease in the number of intrarenal vessels, but if loss of estrogen contributes to this microvascular, rarefaction remains unclear. We tested the hypothesis that the decreased renal microvascular density with age is aggravated by loss of estrogen. Six-month-old female C57/BL6 mice underwent ovariectomy (Ovx) or sham operation and then were allowed to age to 18 -22 mo. Another comparable group was replenished with estrogen after Ovx (OvxϩE), while a 6-mo-old group served as young controls. Kidneys were then dissected for evaluation of microvascular density (by micro-computed tomography) and angiogenic and fibrogenic factors. Cortical density of small microvessels (20 -200 m) was decreased in all aged groups compared with young controls (30.3 Ϯ 5.8 vessels/mm 2 , P Ͻ 0.05), but tended to be lower in sham compared with Ovx and OvxϩE (9.9 Ϯ 1.7 vs. 17.2 Ϯ 4.2 and 18 Ϯ 3.0 vessels/mm 2 , P ϭ 0.08 and P ϭ 0.02, respectively). Cortical density of larger microvessels (200 -500 m) decreased only in aged sham (P ϭ 0.04 vs. young control), and proangiogenic signaling was attenuated. On the other hand, renal fibrogenic mechanisms were aggravated in aged Ovx compared with aged sham, but blunted in OvxϩE, in association with downregulated transforming growth factor-␤ signaling and decreased oxidative stress in the kidney. Therefore, aging induced in female mice renal cortical microvascular loss, which was likely not mediated by loss of endogenous estrogen.

BACKGROUND Hypertension (HTN) may lead to left ventricular hypertrophy and vascular dysfunction, which are independent factors for adverse cardiovascular outcomes. We hypothesized that decreased blood pressure by percutaneous transluminal renal angioplasty (PTRA) would improve the function and architecture of coronary microvessels, in association with decreased inflammation and fibrosis. METHODS Three groups of pigs were studied: normal, HTN, and HTN+PTRA. After 6 weeks of renovascular HTN, induced by placing a local-irritant coil in the renal artery, pigs underwent PTRA or sham. Four weeks later multidetector-computed tomography (CT) was used to assess systolic, diastolic, and microvascular function, and responses to adenosine. Microvascular architecture, oxygen sensors, inflammation, and fibrosis were then explored in cardiac tissue. RESULTS PTRA successfully decreased blood pressure and left ventricular hypertrophy. Basal fractional vascular volume (FVV) was similar among the groups, but its response to adenosine was significantly attenuated in HTN, whereas microvascular permeability (MP) and response to adenosine were greater than normal. Both were restored by PTRA. These were accompanied by increased myocardial expression of hypoxia-inducible factor (HIF)-1α, inflammation, and microvascular remodeling, including increased density of epicardial microvessels (20–200 µm), as well as cardiac diastolic dysfunction, all of which improved by reversal of HTN. However, PTRA only partially decreased myocardial fibrosis. CONCLUSIONS Reversal of early renovascular HTN improved coronary microvascular function and architecture and reversed myocardial hypertrophy and diastolic dysfunction, in association with decreased levels of myocardial ischemia and inflammation markers, underscoring the benefits of blood pressure normalization for preservation of cardiovascular function and structure.