Small Vessels, Big Role
2017; Lippincott Williams & Wilkins; Volume: 69; Issue: 4 Linguagem: Alemão
10.1161/hypertensionaha.116.08319
ISSN1524-4563
Autores Tópico(s)Chronic Kidney Disease and Diabetes
ResumoHomeHypertensionVol. 69, No. 4Small Vessels, Big Role Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBSmall Vessels, Big RoleRenal Microcirculation and Progression of Renal Injury Alejandro R. Chade Alejandro R. ChadeAlejandro R. Chade From the Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, Department of Medicine, and Department of Radiology, University of Mississippi Medical Center, Jackson. Search for more papers by this author Originally published13 Feb 2017https://doi.org/10.1161/HYPERTENSIONAHA.116.08319Hypertension. 2017;69:551–563Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 Chronic kidney disease (CKD) is a growing health problem. Data from the US Renal Data System Reports show that the number of patients enrolled in end-stage renal disease (ESRD) Medicare-funded programs increased to a staggering 60-fold during the last 4 decades1–4 and now consumes a significant portion of the healthcare budget. Despite the magnitude of resources dedicated to treatment of chronic renal disease and the substantial improvements in the quality of dialysis and coadjuvant therapeutic strategies, these patients experience significant reductions in their quality of life, increased morbidity, and higher mortality. Furthermore, a recent projection shows that the incidence and prevalence of CKD may continue to increase in coming decades.5 This somber scenario emphasizes the need for a better understanding of underlying mechanisms of renal injury and the development of novel interventions and strategies to slow the onset and progression of CKD.Microvascular networks are dynamic anatomic units that are tightly balanced to provide nutrition and remove waste products to meet the metabolic and functional demands of each tissue. In the kidney, the glomerular and peritubular capillaries also command glomerular filtration, tubular reabsorption, and recirculation of body fluids, nutrients, hormones, and other substances to the body.6,7 Endothelial dysfunction as well as functional and structural rarefaction8 of the renal microvessels play a prominent role in inducing renal injury associated with major cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, and atherosclerosis. Furthermore, a defective renal microcirculation is a universal pathological feature in CKD that progresses as CKD evolves and compromise both the renal nutrition and renal function.6,7The current review will focus on the role of microvascular disease in the progression of renal injury. It will discuss the involvement of microvascular disease as both cause and consequence of pathological mechanisms affecting the kidney. Finally, I will also discuss the potential of therapeutic interventions to protect the renal microvasculature using clinically available and experimental treatments. Although promising,9–15 the success of targeted microvascular therapies may depend on how severe and extensive the microvascular damage is and mainly, whether glomeruli are lost or still viable, narrowing the window of opportunity to change the progressive nature of CKD/ESRD.Epidemiology, Major Causes, and Pathological Contributors to CKDThe emergent population of CKD/ESRD patients in recent years is linked to dramatic increases in obesity and obesity-associated cardiovascular risk factors, such as lipid abnormalities, atherosclerosis, diabetes mellitus, and hypertension. Although these comorbid conditions may develop separately, they often coexist and may potentiate injury of target organs, including the kidneys, in an additive or synergistic fashion.7,16,17Recent reports from the Centers for Disease Control,18 the National Institutes of Health,19 and the World Health Organization20 show that obesity has more than doubled since 1980. Currently, 68.8% of adults in the United States are overweight or obese19 (with a slightly higher prevalence in women: 40.4% versus 35%21), with 6% to 8% of them having extreme obesity (body mass index >40). Furthermore, ≈33% of the US children and adolescents are overweight and >18% are obese.18,19 Unfortunately, the prevalence (and consequently, impact) of obesity will likely continue to increase unless these trends can be reversed because ≈80% of obese children may become obese adults with the associated increased susceptibility to develop cardiovascular, metabolic, and kidney diseases.Dyslipidemia and atherosclerosis are parts of a chronic and systemic inflammatory process that compromises the function and structure of small and large vessels. They are frequently associated with chronic renal disease and may serve as cause and as consequence of CKD. Not only by the build-up of atherosclerotic plaques, but also at preceding stages of vascular fatty streaks or microscopic lipid accumulation, dyslipidemia may promote vascular dysfunction and early remodeling in several vascular beds, including the kidneys. Indeed, microvascular and glomerular dysfunction may precede the onset and represent the silent phase of chronic renal disease.22,23 Experimental studies indicate that diet-induced lipid abnormalities lead to renal endothelial dysfunction, intrarenal inflammation, fibrosis, and a significant vascular dysfunction, damage, and remodeling22–25 on renal vasculature. Furthermore, recent studies showed that dyslipidemia superimposed on experimental renal artery stenosis can not only accelerate renal microvascular dysfunction and remodeling, but also accelerate microvascular loss, underscoring ample deleterious effects of atherogenic factors on the renal parenchyma.23,26The major causes of CKD and ESRD are diabetes mellitus and hypertension, which lead to progressive microvascular damage and loss and set the stage for evolving renal injury.27–30 Hypertension is the second leading cause of CKD/ESRD in the United States after diabetes mellitus, is estimated to affect 1 billion people worldwide, and is responsible of 9 million deaths per year.31 The recent SPRINT study (Systolic Blood Pressure Intervention Trial) demonstrated that aggressive control of blood pressure decreases risk for cardiovascular events and even death,32 which underscores the pathophysiological importance of hypertension and its priority for treatment. The effect of high blood pressure on the renal vessels is a major driving force for the early development of vascular remodeling in both large and small vessels, which precedes, predicts, and significantly contributes to development of overt renal abnormalities.33–35 Diabetes mellitus is the number one cause of CKD/ESRD and has almost quadrupled in the last 3 decades, affecting 422 million adults worldwide. These staggering numbers are largely because of the rise in type 2 diabetes mellitus, which accounts for ≤95% of the 25.8 million cases of diabetes mellitus in the United States and is driven by overweight and obesity.36 The development and mechanisms of diabetes mellitus–induced renal injury and progression toward diabetic nephropathy have been reviewed and discussed elsewhere37,38 and are beyond the scope of this review. However, it is important to emphasize that, as in hypertension, renal microvascular abnormalities in diabetes mellitus also lead and foresee the deterioration of renal function, underscoring the central role of microvascular disease in development and progression of renal injury.27,29Life expectancy has significantly increased in the past 50 years.39 Aging carries a physiological decline in renal function, which may be accelerated or aggravated by comorbid conditions. Indeed, with time, the kidney shows an age-associated reduction of function disclosed by a progressive (but widely variable) decline in glomerular filtration rate and renal blood flow, which is possibly driven by reduced renal bioavailability of nitric oxide (NO) and often associates with different degrees of renal parenchymal damage.40 Importantly, most of these changes are driven by functional and structural changes of the renal microcirculation at the pre- and postglomerular level, an increase in glomerular capillary hydraulic pressure, and parenchymal changes that lead to loss of renal mass, microvascular remodeling, and tubule–interstitial fibrosis.41,42 Although such changes do not always translate into CKD and may not require interventions in a disease-free individual, they can increase the susceptibility of the aging kidney to acute kidney injury and make it more labile for the development of CKD.40,41Renal Microvascular NetworkProgressive ramifications from the main renal artery branch into interlobar, arcuate, and interlobular arteries toward the smaller branching afferent arterioles leading to the glomerular capillaries where fluid and solutes are filtered (except for plasma proteins). Then, the distal ends of the glomerular capillaries converge to form the efferent arterioles, which are followed by a second capillary network, the peritubular capillaries, which are key components for filtration, secretion, and reabsorption of minerals and removal of waste from the filtered blood that will be excreted by urine. On the venous side, the small veins run in parallel to the arterioles to subsequently form the interlobular, arcuate, interlobar, and renal vein, which leaves the kidney beside the renal artery and ureter. This unique vascular network deals with ≈1.1 L/min of the cardiac output, and only 10% of the delivered oxygen is normally sufficient to satisfy the renal metabolic demands.6 Thus, the majority of the workload on the renal microvascular networks is to maintain body homeostasis, which underscores the importance of renal function in health and disease.The intrarenal microvascular network may be disrupted from a functional or a structural angle. Microvascular rarefaction is defined as a reduction of available vessels, which can be divided into functional (the vessels are anatomically present but with a deficient or absent perfusion) and structural (anatomic reduction in the number of vessels in the tissue) rarefaction.8 A study by Bohle et al43 demonstrated in biopsies of patients with chronic renal disease from different etiologies a significant inverse relationship between the number and area of the cortical tubular capillaries and their serum creatinines, showing that microvascular rarefaction develops in human CKD and negatively correlates with renal dysfunction.It is important to emphasize that these 2 forms of microvascular rarefaction are not mutually exclusive, can coexist, and can be parts of a progressive process that goes from dysfunction to loss of microvessels. A potential bridge between functional and structural rarefaction could be defined as microvascular remodeling, in which anatomic changes in the microvascular wall develops, progressively contributes to disrupt microvascular function, and may lead to microvascular loss. Finally, renal microvascular rarefaction may also develop as a physiological event in the aging kidney and is suggested as a major determinant in the decreased renal blood flow and glomerular filtration rate 44 associated with age. Therefore, because smaller arterioles and capillaries are primary targets of acute or chronic insults11,12,45,46 and their damage may affect renal hemodynamics, function, and progression of renal injury, microvascular rarefaction (functional and structural, physiological, or pathological) plays an important role in the progression of renal injury, regardless of the primary etiology.Mechanisms of Kidney Injury Driven by Microvascular RarefactionWork in Progress: Microvascular Endothelial DysfunctionRenal microvascular endothelial dysfunction is a central mechanism driving functional rarefaction because it may contribute to the transition from functional to structural rarefaction. It results from abnormal function of endothelial cells combined with reduced availability of substances that are produced by or act on the endothelium to determine vascular tone, permeability, fluid balance, and cell proliferation.47,48 Endothelial dysfunction develops early in cardiovascular and renal disease and is a consequence and a contributor for the development and progression of hypertension, diabetes mellitus, atherosclerosis, and chronic heart and renal pathologies.49–52A central player in endothelial dysfunction is deficiency of NO, a gaseous molecule that controls vascular tone and regulates inflammatory and coagulant properties of the endothelium (beyond the scope of this review). A reduced availability of NO may be the result of altered production from major sources, such as endothelial NO synthase (eNOS) or augmented NO removal. Studies from Goligorsky et al53,54 demonstrated that inhibition of NOS and deficiency of NO are powerful profibrotic stimuli that increase endothelial to mesenchymal transdifferentiation and may contribute to microvascular endothelial dysfunction and subsequent microvascular rarefaction. Furthermore, an altered production by eNOS can also result from a lack of a key cofactor, such as tetra-hydrobiopterin, which results in eNOS uncoupling and switches eNOS from production of NO to generation of reactive oxygen species (ROS).55 In turn, ROS decrease renal microvascular bioavailability of NO through ROS-mediated quenching effects.56 Factors that favor deleterious ROS-NO interactions in the kidney include excessive activation of the renin–angiotensin–aldosterone and endothelin systems.55,57 These systems play important physiological roles in controlling renal hemodynamics but are often upregulated in cardiovascular and renal disease and contribute to vasoconstriction and endothelial dysfunction directly and via stimulation of ROS production. Increased ROS may in turn stimulate production and activation of redox-sensitive proinflammatory and profibrotic factors in the kidney, such as nuclear factor kappa-B, tumor necrosis factor-α, transforming growth factor-β, or connective tissue growth factor, to name a few, which are often involved in the development and progression of renal injury.22–24,58 Thus, ROS-mediated reduction in renal NO takes center stage in pathological effects associated with endothelial dysfunction and may promote vasoconstriction, vascular inflammation, and tissue damage,59 which in turn further reduce NO bioavailability and perpetuates a vicious circle.Work in Progress: From Microvascular Constriction to Microvascular RemodelingIn parallel, a dysfunctional or damaged endothelium may lead to a sustained renal vasoconstriction, which may lead to inadequate intrarenal nutrition, as well as compromised renal hemodynamics and function. A prolonged vasoconstriction of intrarenal microvessels may lead to inward remodeling, a structural microvascular alteration that is a prominent mechanism for the development and progression of renal damage in hypertension and renal ischemia.60–62 Our previous studies in a model of chronic renovascular hypertension and renovascular disease demonstrated that progressive renal injury associates with significant intrarenal microvascular remodeling, disclosed by increased microvascular media-to-lumen ratio, perivascular fibrosis, and decreased microvascular diameter.23,60,63 Such changes in the kidney microvasculature were mainly observed in those vessels under 200 μm in diameter, which suggest that pre- and postglomerular microvessels are susceptible targets and likely contributors to development of renal injury.A combination of a sustained vasoconstriction and a proinjurious milieu likely pave the way for progression of functional rarefaction toward microvascular remodeling and eventually loss of the smaller vessels, which may contribute to further renal injury. Furthermore, a recent study demonstrated that renal endothelial cells show a distinctly poor endogenous proliferative ability, which may play a role in the limited intrinsic regenerative capacity of renal capillaries64 and may significantly contribute to the progressive nature of renal microvascular rarefaction. However, studies have also shown that therapeutic interventions using different compounds such as clinically available antioxidant vitamins, statins, endothelin receptor or renin–angiotensin–aldosterone blockers, or experimental agents can preserve or recover endothelial function, improve renal hemodynamics, and reduce the development and progression of renal injury in hypertension, diabetes mellitus, atherosclerosis, acute, and chronic renal injury.4,12,24,45,65–70 It is important to emphasize that such improvements are often accompanied by attenuated remodeling of the renal microvascular architecture, underscoring the notion that microvascular disease is an evolving process that, if unattended, actively participates on the progression of renal damage. Moreover, microvascular remodeling may also diminish the efficacy of therapeutic interventions,61 suggesting a potential tipping point of microvascular damage that could limit recovery and lead to the progression toward irreversible tissue damage and loss of function.Renal Microvascular Loss: Cause and Consequence of Progressive Renal DamageLoss of the microvasculature in any tissue or organ may reflect the final stage of progressive loss of microvascular homeostasis paired with disruption of healing mechanisms. Indeed, plasticity of the renal microcirculation to adapt to a new environment or to generate from preexisting vasculature as needed are important characteristics that may be lost as diseases progress, as can be observed in atherosclerosis,25 ischemia,12,63 or diabetes mellitus–induced renal injury.29One of the pivotal players for maintenance and repair of microvascular networks everywhere, including the kidney, is VEGF (vascular endothelial growth factor). This proangiogenic cytokine plays important roles in the kidney that go beyond vasculoprotective effects.3,71 VEGF is highly ubiquitous, and the renal cells are sources and targets of this cytokine. Major sources of renal VEGF are tubular epithelial cells and podocytes, and major targets are endothelial cells and podocytes as well, suggesting renal autocrine and paracrine effects.3,72,73Progressive dysfunction, damage, and loss of endothelial cells and glomeruli and peritubular microvascular drop-out paired with a marked reduction of VEGF expression have been described in clinical74 and experimental settings.15,75–77 Altered expression and availability of renal VEGF coupled with microvascular abnormalities has been demonstrated in CKD, renal ischemia, early diabetic-induced renal injury, and diabetic nephropathy.11,27,29,78 The decreased renal bioavailability likely results from loss of renal sources VEGF (eg, proximal tubular cells, podocytes3,11), altered VEGF-upstream signaling,63 and possibly, disruption of post-translational mechanisms of VEGF.12 The decrease in renal VEGF also affects the VEGF receptors-mediated downstream angiogenic signaling, as shown by the blunted expression of renal angiopoietins, Akt (protein kinase B), and ERK1/2 (extracellular signal-regulated kinase 1 and 2), which are prominent mediators of endothelial cell survival, proliferation, and maturation of newly generated vessels.9 Furthermore, insufficient or reduced renal VEGF may also have a major impact on preceding steps that involved mobilization and homing of cell progenitors toward microvascular repair, proliferation, and tissue healing.13 Indeed, a decrease in renal VEGF also drives the blunted expression of stromal-derived factor 1, angiopoietins, and Oct-4 (octamer binding transcription factor 4), which are prominent factors involved in progenitor cell biology that are all recovered after improving VEGF signaling.9,13,15 Therefore, in a context of blunted renal bioavailability of VEGF, the impetus for microvascular proliferation and repair is severely diminished, leading to a reduction in renal microvascular density, and may become a central progressive mechanism of renal parenchymal damage.The renal microvascular network can also be disturbed or reduced by other mechanisms. Hepatocyte growth factor (HGF) is a pleiotropic cytokine with distinct renoprotective roles, as has been demonstrated in diabetes mellitus–induced renal injury and in acute and chronic renal ischemia.10,79,80 HGF promotes tissue healing by stimulating mobilization of cell progenitors, by interactions with VEGF81 to promote microvascular proliferation and repair, and by counteracting renal inflammation, fibrosis, and apoptosis via transforming growth factor-β, nuclear factor kappa-B, and Bax/BcL (B cell lymphoma-2 associated X protein) inhibition.10,80,82–84 Reduced bioavailability of this factor significantly accelerates development of microvascular rarefaction, renal inflammation, and fibrosis,10,80,83 supporting an important role of HGF to protect the renal parenchyma and preserve the renal microvasculature.Renal fibrosis is the common pathway of advanced renal disease that is closely related to microvascular rarefaction. A recent study from Ehling et al85 using 3 different mouse models of progressive renal disease showed that abnormalities in the renal microvascular function and structure, such as reductions in microvascular diameter and increased microvascular tortuousity, develop early and may precede and contribute to development of renal fibrosis, supporting a prominent role of microvascular abnormalities as a possible universal mechanism for progression of tissue damage. Fibrosis is the loss of functional tissue that is replaced by nonfunctional scarred tissue that reflects a marked imbalance between extracellular matrix (ECM) production and degradation toward ECM accumulation. The renal accumulation of ECM in turn may induce powerful effects on renal microvascular development, proliferation, and function86 directly and via increasing antiangiogenic products. Indeed, the ECM is a rich source of factors that may diminish microvascular proliferation and repair, such as endostatin, a potent inhibitor of angiogenesis and VEGF and a prominent contributor to microvascular rarefaction in CKD.87 Another ECM-related antiangiogenic factor that may contribute to renal microvascular loss is angiostatin,9 a potent proapoptotic and anti-VEGF factor that can contribute to the development of tubular and interstitial damage by inducing capillary fragility and dropout.88,89 These antiangiogenic factors may interfere with VEGF and reduce microvascular repair and proliferation, which may negatively impact renal tissue healing and functional recovery independent of the initial insult. In depth discussion of molecular mechanisms of renal fibrosis are beyond the scope of this review, and readers are suggested to consult published literature.90,91Another pathway to renal microvascular loss is apoptosis or programed cell death, a prominent mechanism by which podocytes3 and renal endothelial and epithelial cells may be killed when facing acute or chronic ischemia and a contributor for the progression of vascular dropout and tubular injury.92,93 An ischemic/hypoxic renal milieu may stimulate apoptosis and, thus, exacerbate renal injury via the intrinsic (caspase-dependent) and extrinsic (caspase-independent) pathways.3,4,94 Apoptosis of renal endothelial cells could be driven and enhanced by a reduction in bioavailability of angiogenic factors, such as VEGF or HGF, which not only stimulates migration and proliferation, but also promotes cell survival via powerful antiapoptotic effects.95–97 In turn, ischemic-induced apoptosis of podocytes may contribute to the loss of renal VEGF,3 which may further accelerate endothelial cell death and reduce compensatory renal microvascular proliferation and repair. Our recent studies in a swine model of chronic renal artery stenosis showed that a reduced expression of these factors in the ischemic kidney parallels increased apoptotic activity and apoptotic cells, progressive microvascular rarefaction, and evolving renal dysfunction and damage.4,11,66 Thus, apoptosis may serve as an important contributor for renal microvascular endothelial cell damage and loss, development of microvascular rarefaction, and may increase the risk for progression of renal injury. However, unlike necrosis, apoptosis is an energy-dependent mechanism of cell death, and the extent of its pathophysiological role in microvascular damage and loss may be context-dependent and determined by the severity of the initial renal insult and development of renal disease.94Therapeutic Strategies: Is Protection of Renal Microvessels Feasible?Severity of microvascular damage and loss may define the limits between reversible and irreversible renal injury, and success in restoring kidney function may depend on how far microvascular rarefaction has progressed (Figure 1). The different degrees of microvascular dysfunction and damage, which may in turn depend on the extent of the initial insult or length of the disease, may offer an opportunity for therapeutic targeting of renal microvascular disease to stimulate microvascular repair and peritubular and glomerular capillary regrow. Evidence from our laboratory supports the notion that renal functional and structural damage could be ameliorated by targeted interventions that reverses renal microvascular rarefaction9,11,15 (Figure 2). However, such approach may need to be initiated before the entire glomerulus is lost. It is possible that generation of new vessels that shunt preexisting damaged ones and stimulation of microvascular repair may contribute to restoration of blood flow and to improve glomerular filtration rate in partly damaged or hibernated but recoverable nephrons.99,100Download figureDownload PowerPointFigure 1. Schematic overview of the progressive nature of chronic kidney disease (CKD) and contributions of microvascular (MV) rarefaction to the process. Regardless of the etiology (eg, hypertension, diabetes mellitus, atherosclerosis, obesity), CKD universally associates with MV rarefaction. A progressive damage of the microcirculation deteriorates renal hemodynamics and perfusion, leading to a progressive loss of filtration, tubular function, and development of fibrosis, which in turn serves as a feedback mechanism that may further accelerate progression of CKD toward irreversible renal injury. Therapeutic interventions (gray box, clinically available or experimental) to protect the renal MV architecture and function (remodeling, rarefaction, regeneration, and repair) may be more effective to improve renal function and slow the progression of CKD if applied before severe reductions in renal blood flow and nephron loss (above red dotted lines).Download figureDownload PowerPointFigure 2. Representative image showing renal fibrosis (top, ×20) and 3D micro-CT reconstruction of the renal microvascular (MV) architecture (bottom), tomographically isolated microvessels (yellow arrow, bottom), and cross sections of microfilm-perfused kidneys (orange arrow, bottom; stereo-microscopy, ×20) in normal, stenotic kidney, and stenotic kidney after vascular endothelial growth factor (VEGF) therapy. The stenotic kidney has a significant MV loss, increased MV tortuousity, MV remodeling, and fibrosis after 10 weeks of renal artery stenosis. A single intrarenal administration of VEGF after 6 weeks of renal artery stenosis largely reversed most of these changes (quantified 4 weeks later). Visibly perfused glomeruli correlates with changes in density of renal MV. CT indicates computerized tomography; and G, glomeruli. Adapted from Chade.98 Copyright © 2011, the American Physiological Society.Microvascular protection or targeted renal microvascular angiogenesis strategies are not yet fully developed, and therefore, current therapies have not focused on preventing rarefaction of the renal microcirculation. This section will discuss the effects of clinically available and experimental therapies and their effects on renal microvascular function.Direct and Indirect Microvascular Protection: Antihypertensive, Antidiabetic, and Lipid-Lowering DrugsDiabetes mellitus, hypertension, and lipid abnormalities are major causes of CKD. Therapeutic agents often used in these diseases display effects on microvascular function, remodeling, and even proliferation, which seem to be a pleiotropic effect of these compounds. Previous studies demonstrated that insulin,101 angiotensin receptor blockers,102 or statins60 play important roles in regulating endothelial function, vascular tone, and tissue perfusion by preserving or stimulating production of NO in endothelium and microvascular perfusion in different organs. Furthermore, other studies showed that the effects of these agents may also extend to attenuating microvascular remodeling and even promoting microvascular proliferation in several vascular beds like in the heart and kidney.60,68,103,104 Therefore, part of the renoprotective effects of these agents may result from preserving renal microvascular function and integrity, directly or indirectly, as well as from controlling risk factors, such as hyperglycemia, high blood pressure, and dyslipidemia.For example, studies showed that insulin, beyond glucose control, may stimulate NO generation and proangiogenic activity in endothelial cells (eg, migration, tube formation105), which may be a prominent mechanism in insulin-mediated healing actions in different tissues106,107 that seems to be independent of VEGF signaling.108 Similar stimulatory effects on angiogenesis has been described in experimental settings, both in vitro and in vivo, for new generation of clinically available oral antidiabetic drugs, such as sitagliptin,109 and for glucagon-like
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