Citations

Abstract 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 poststenotic kidney by blunting different disease pathways. Peripheral blood EPC and adipose-derived MSC were expanded and characterized by cell surface markers (e.g., CD34/kinase insert domain receptor, 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 intrarenal infusion of vehicle (n = 7), EPC (RAS+EPC) or MSC (RAS+MSC) (both 10 × 106, 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 cocultured with EPC and MSC. 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. 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.

Background— The selection of patients with renal artery stenosis (RAS) likely to improve glomerular filtration rate (GFR) after percutaneous transluminal renal angioplasty is difficult. We examined basal hemodynamic and inflammatory factors linked to improved stenotic kidney (STK) function after percutaneous transluminal renal angioplasty in swine RAS. Methods and Results— Fifteen pigs after 6 weeks of hemodynamically significant RAS were studied before and 4 weeks after technically successful percutaneous transluminal renal angioplasty+stenting. STK and contralateral kidney hemodynamics and function were evaluated by multidetector computed-tomography before and after acetylcholine challenge. Single-kidney deoxyhemoglobin (R2*, reciprocal to blood relaxation) and energy-dependent tubular function were assessed using blood-oxygen-level–dependent magnetic resonance imaging before and after furosemide. Baseline renal vein and inferior vena cava levels of inflammatory markers were measured and their gradient and net release calculated. Baseline parameters were compared with normal (n=7) and sham-RAS (n=7) pigs and correlated with the change in STK-GFR after revascularization (ΔGFR). Four weeks after percutaneous transluminal, renal angioplasty blood pressure was normalized in all animals, but STK-GFR improved in 10 of 15 (ΔGFR =+22.0±8.5 mL/min). ΔGFR correlated inversely with basal STK-GFR, renal release of inflammatory markers, and medullary R2* response to furosemide, but directly with GFR response to acetylcholine. Basal contralateral kidney GFR correlated directly with ΔGFR. Conclusions— Low basal STK-GFR with preserved response to acetylcholine may predict benefit from revascularization in RAS, whereas renal inflammation and robust STK-R2* responses to furosemide (possibly reflecting avid tubular oxygen consumption) are associated with less favorable outcomes. These tools may be useful for identification of patients likely to improve renal function after revascularization.

Revascularization improves blood pressure but not renal function in most patients with atherosclerotic renal artery stenosis (ARAS), possibly related to injury incurred during renal reperfusion. Bendavia, a novel tetrapeptide that inhibits mitochondrial permeability transition pore opening, reduces apoptosis, oxidative stress, and ischemia-reperfusion injury in experimental models. However, its potential for improving renal response to revascularization of chronic ARAS is unknown. We hypothesized that adjunct Bendavia would improve renal structure and function after percutaneous transluminal renal angioplasty (PTRA). Pigs were treated after 6 weeks of ARAS or control with PTRA+stenting (or sham), adjunct continuous 4-hour infusion of Bendavia (0.05 mg/kg IV) or vehicle (n=7 each) during PTRA. Single-kidney renal blood flow and glomerular filtration rate were studied 4 weeks later and renal mitochondrial biogenesis, microvascular architecture, and injurious pathways evaluated ex vivo. Monocyte chemoattractant protein-1 levels rose after PTRA, suggesting inflammatory injury. Bendavia did not immediately affect inflammatory cytokine levels, yet 4 weeks later, stenotic kidney renal blood flow and glomerular filtration rate both improved (44.00 ± 0.21% and 36.40 ± 10.21%, respectively) in ARAS+PTRA+Bendavia compared with ARAS+PTRA+vehicle. Renal mitochondrial biogenesis was restored after PTRA+Bendavia, and microvascular rarefaction, apoptosis, oxidative stress, tubular injury, and fibrosis decreased. Infusion of Bendavia during PTRA preserved mitochondrial biogenesis, renal hemodynamics, and function, and attenuated tissue injury in swine ARAS. Thus, functional mitochondrial injury during renal reperfusion may sustain renal inflammatory injury and limit kidney recovery after PTRA. Potent antiapoptotic and antioxidant effects provide Bendavia a novel therapeutic potential for improving kidney outcomes after PTRA in experimental ARAS.

Background— Coronary stents, drug-eluting stents in particular, have been linked to coronary epicardial endothelial dysfunction after implantation. However, less is known about their impact on coronary microvascular function and their long-term effects on the vasculature. Methods and Results— We evaluated 71 patients (mean age, 53.0±10.1 years) with chest pain and angiographically nonsignificant coronary artery disease 17.1±17.1 months after left anterior descending coronary artery stenting. Seventy-one age- and sex-matched patients (mean age, 53.0±10.3 years) with chest pain but no prior coronary intervention served as controls. Coronary blood flow in response to the endothelium-dependent vasodilator acetylcholine as well as the microvascular (endothelium-independent) coronary flow reserve in response to intracoronary adenosine were evaluated. Quantitative coronary angiography was used to study epicardial diameter changes to acetylcholine. Microcirculatory function was not significantly different between the stenting and control groups (median [interquartile range] coronary flow reserve, 2.9 [2.5–3.4] versus 3.0 [2.4–3.4] mL/min, P =0.24; change of coronary blood flow, 34.9% [−34.4% to 90.0%] versus 54.7% [−5.6% to 104.6%], P =0.18). Both groups exhibited epicardial endothelial dysfunction (−23.0% [−47.4% to −7.6%] versus −20.0% [−40.0% to 0.0%], P =0.4). Results did not differ between patients with drug-eluting stents (n=46) and patients with bare-metal stents (n=24). Conclusions— This study demonstrates that in patients with coronary arteries in which a stent has been placed, coronary microcirculatory and epicardial vascular function are not significantly different from that of an age- and sex-matched population with similar symptoms but nonsignificant coronary artery disease.