transforming-growth-factor-beta and Renal-Artery-Obstruction

Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells-derived extracellular vesicles (EVs). The anti-inflammatory TGF-β (transforming growth factor-β) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-β expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8

Topics: Animals; Coculture Techniques; Cytokines; Dietary Carbohydrates; Dietary Fats; Extracellular Vesicles; Female; Inflammation; Infusions, Intra-Arterial; Metabolic Syndrome; MicroRNAs; Monocytes; Random Allocation; Renal Artery; Renal Artery Obstruction; Renal Circulation; Renal Insufficiency, Chronic; Signal Transduction; Swine; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow and is a potential cause of chronic kidney injury, yet little is known regarding inflammatory pathways in this disorder in human participants. This study aimed to examine the hypothesis that reduced renal blood flow (RBF) in ARAS would be associated with tissue TGF-β activation and inflammatory cell accumulation.. This cross-sectional study of ARAS of varying severity compared transjugular biopsy specimens in patients with ARAS (n=12, recruited between 2008 and 2012) with tissue from healthy kidney donors (n=15) and nephrectomy specimens from individuals with total vascular occlusion (n=65). ARAS patients were studied under controlled conditions to measure RBF by multidetector computed tomography and tissue oxygenation by blood oxygen level-dependent magnetic resonance imaging.. Compared with the nonstenotic contralateral kidneys, RBF was reduced in poststenotic kidneys (242±149 versus 365+174 ml/min; P<0.01) as was single-kidney GFR (28±17 versus 41±19 ml/min; P<0.01), whereas cortical and medullary oxygenation were relatively preserved. Tissue TGF-β immunoreactivity was higher in ARAS patients compared with those with both normal kidneys and those with total occlusion (mean score 2.4±0.7 versus 1.5+1.1 in the nephrectomy group and versus 0±0 in donors; P<0.01). By contrast, the number of CD68+ macrophages was higher with greater disease severity (from 2.2±2.7 in normal to 22.4±18 cells/high-power field in nephrectomy samples; P<0.001).. The results of this study indicate robust stimulation of TGF-β associated with macrophage infiltration within the human kidney with vascular occlusive disease.

Topics: Aged; Atherosclerosis; Biopsy; Female; Fibrosis; Humans; Kidney Transplantation; Macrophages; Male; Middle Aged; Nephrectomy; Nephritis, Interstitial; Renal Artery Obstruction; Renal Circulation; Renal Insufficiency, Chronic; Tissue Donors; Transforming Growth Factor beta

Although the two-kidney, one-clip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the well-established role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P = not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.

Topics: Animals; Atrophy; Collagen; Constriction, Pathologic; Fibrosis; Hypertension, Renovascular; Immunohistochemistry; Kidney; Kidney Function Tests; Mice; Mutation; Real-Time Polymerase Chain Reaction; Renal Artery Obstruction; Renal Circulation; Renin; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Advanced renal artery stenosis (RAS) may cause progressive deterioration in renal function. We correlated the histopathological findings and clinical characteristics in selected patients with atherosclerotic RAS who underwent nephrectomy of their small kidneys for resistant renovascular hypertension.. We studied 62 patients who underwent nephrectomy of a small kidney for uncontrolled hypertension between 1990 and 2000.. The mean patient age was 65.4 ± 9.6 years; 28 (45%) were men. Significant tubulointerstitial atrophy with relative glomerular sparing was the predominant pattern of injury in 44 (71%) patients. In 14 (23%) patients, diffuse global glomerulosclerosis was present. The severity of tubulointerstitial atrophy and the extent of glomerulosclerosis were both associated with smaller kidney size (P = 0.002). Three patterns of vascular involvement were present: atheroembolic, atherosclerotic and hypertensive vascular changes, which were documented in 39, 98 and 52% of subjects, respectively. The presence and severity of these vascular changes positively correlated with both atherosclerotic risk factors, such as hypertension, dyslipidaemia and renal insufficiency, and cardiovascular morbidity, including abdominal aortic aneurysm and myocardial infarction. Patients on statin therapy were noted to have less evidence of renal fibrosis as measured by transforming growth factor-beta staining (P = 0.003).. The severity of renal histopathological findings in patients who underwent nephrectomy for resistant hypertension correlated with an increased prevalence of cardiovascular disease, a greater degree of renal dysfunction and more severe dyslipidaemia. Statin therapy may affect development of intra-renal injury by slowing the progression of fibrosis.

Topics: Aged; Arteriosclerosis; Female; Fibrosis; Humans; Hypertension, Renal; Ischemia; Kidney; Male; Middle Aged; Renal Artery Obstruction; Transforming Growth Factor beta

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.. Single-kidney hemodynamics and function were quantified in vivo with electron-beam computed tomography in 3 groups of pigs (n=7 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 (HC+RAS, 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 HC+RAS ischemic kidneys, accompanied by similar increased expression of profibrotic factors like transforming growth factor-beta, tissue inhibitor of metalloproteinase-1, and plasminogen activator inhibitor-1. Nevertheless, HC+RAS kidneys showed increased intrarenal fibrosis compared with RAS-only kidneys. Furthermore, expression of nuclear factor-kappaB was increased, expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems was decreased, and apoptosis was blunted.. 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.

Topics: Animals; Arteriosclerosis; Fibrosis; Glomerular Filtration Rate; Hypercholesterolemia; Kidney; Matrix Metalloproteinase 2; NF-kappa B; Plasminogen Activator Inhibitor 1; Receptors, LDL; Receptors, Oxidized LDL; Renal Artery Obstruction; Renal Circulation; Swine; Tissue Inhibitor of Metalloproteinase-1; Tomography, X-Ray Computed; Transforming Growth Factor beta

Topics: Humans; Hypertrophy; Infant; Juxtaglomerular Apparatus; Renal Artery Obstruction; Renin; Thrombosis; Transforming Growth Factor beta