commentary
http://www.kidney-international.org & 2014 International Society of Nephrology
see basic research on page 276
HIF meets NF-jB signaling Carsten Willam1 An inflammatory stimulus prior to an ischemic insult can be protective in acute kidney injury (AKI) as well as other acute organ injury models, an effect called cross-tolerance. He et al. investigated mechanisms of cross-tolerance whereby pretreatment with lipopolysaccharide (LPS) protects from a subsequent ischemic insult of the kidney. The protection was mediated by LPS-induced nuclear factor-jB and hypoxia-inducible factor-2a (HIF-2a) signaling. These results link two central cellular pathways and give new insight into HIF-mediated renoprotection in AKI models. Kidney International (2014) 85, 232–234. doi:10.1038/ki.2013.362
Acute ischemia is traditionally thought to be the major pathophysiological event in the pathogenesis of rapidly deteriorating renal function in acute kidney injury (AKI). Ischemia evolves from an acute drop in oxygen supply, often due to low circulatory blood pressure. The kidney is presumably prone to severe ischemia, since, due to oxygen shunting and the postglomerular origin of the descending medullary microvessels, low oxygen tensions are already present in the medullary regions. However, ischemia not only represents simply a lack of energy substrates but is associated with a highly sophisticated regulatory oxygen sensing system in the kidney. This includes induction of more than 200 hypoxia-regulated genes, eventually, but not exclusively, leading to regulation of erythropoiesis and thus to improved oxygen transport throughout the body. The central regulators of this hypoxic response are the transcription factors hypoxia-inducible factors-1 and -2 (HIF-1 and -2) and a group of enzymes that control HIF protein levels, the HIF–prolyl hydroxylase domain enzymes 1 Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen, Germany Correspondence: Carsten Willam, Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. E-mail: [email protected]
232
1–3 (PHD1, -2, and -3), which have been identified as being highly expressed in the kidney. Promisingly, genetic or pharmacological stabilization of HIF, particularly in epithelial cells, impressively demonstrated protective effects in diverse models of experimental AKI. In addition to hypoxia, very convincing data demonstrate a major impact of inflammatory processes on the pathogenesis of ischemic AKI. Ischemic injuries are regularly linked with a marked inflammatory reaction, which leads to invasion of inflammatory cells and release of cytokines. This triggers a complex regulatory cascade that again compromises the homeostasis of the tubulointerstitium. In fact, new insights into inflammatory cascades demonstrated that the inflammatory and the hypoxic gene regulatory pathways may not be regarded as distinct pathophysiological events but are closely linked to each other. In 2003 Cramer et al. already showed that HIF-1a is essential for the inflammatory capacity of myeloid cells, because of the HIF-driven adaptation of glycolysis to metabolic needs. HIF-1 knockout led to a metabolic defect resulting in profound impairment of myeloid-cell aggregation, motility, invasiveness, and bacterial killing.1 Intriguingly, IkB kinase-b (IKKb), which phosphorylates the nuclear factor-kB (NF-kB) inhibitor IkB, is also regulated by the HIF-PHDs2 and
supported NF-kB signaling. Another important finding was that after bactericidal infection or lipopolysaccharide (LPS) exposure, HIF accumulated in inflammatory cells even in the presence of oxygen, implying a link between HIF stabilization and inflammatory NF-kB signaling mediated by Toll-like receptor-2 (TLR2) and TLR4.3 How the TLR-mediated NF-kB signaling translates into HIF stabilization in the presence of oxygen is still less clear. In the search for new molecular pathways to explore novel therapeutic options for protecting from AKI, it has been described that low-dose LPS pretreatment of mice protected from subsequent ischemic or toxic AKI or other organ damage respectively—a phenomenon called cross-tolerance.4,5 Now Kang He, Qiang Xia, and colleagues6 (this issue) demonstrate that LPS exposure prior to ischemia–reperfusion ameliorated AKI in mice (cross-tolerance) and give evidence for the linkage of LPSmediated NF-kB signaling and the HIF pathway in the kidney. Like in previous published studies, LPS pretreatment was protective in ischemia– reperfusion experiments. Importantly, LPS pretreatment led to enhanced HIF2a protein accumulation in kidney extracts. In experiments using Mx1 promoter-driven Cre-mediated conditional HIF knockout mice, only HIF-2a deficiency, not HIF-1a deficiency, abrogated LPS-induced renoprotection, indicating that HIF-2a was responsible for the observed effects. In experiments with human umbilical vein endothelial cells, LPS treatment induced HIF-2a in analogy to the experiments in vivo. This was abolished by the addition of an NF-kB nuclear translocation inhibitor. Hence the authors hypothesize that renoprotective LPS effects were mediated via NF-kB-induced HIF-2a stabilization in endothelial cells (Figure 1). In order to better understand transcriptional downstream effects of HIF-2 accumulation, mice were treated with inhibitors and donators of nitric oxide (NO), which showed that Kidney International (2014) 85, 232–247
commentary
LPS TLR NF-κB HIF-2 iNOS N O N O
Microcirculatory recovery
Figure 1 | Potential model of lipopolysaccharide-mediated crosstolerance in renal endothelial cells. Lipopolysaccharide (LPS) preconditioning induces nuclear factor-kB (NF-kB), which leads to endothelial HIF-2a accumulation. HIF-2a induces inducible nitric oxide synthase (iNOS), which enhances the nitric oxide (NO) level and improves microcirculatory effects in experimental ischemia–reperfusion. TLR, Toll-like receptor.
LPS pretreatment was protective only in the presence of NO in renal tissues. The authors eventually showed that re-establishment of the deteriorated NO synthesis after ischemia–reperfusion by LPS–HIF-2a signaling in the medulla was important for improved postischemic microcirculatory recovery, as assessed by laser Doppler flowmetry. Conversely, inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) expression was significantly reduced in HIF-2 knockout mice, suggesting that LPS effects were mediated via NF-kB-dependent HIF-2a-stimulated NOS expression. The study by He et al.6 can be regarded as a contribution to further unravel AKI pathophysiology and potential protective molecular pathways. Unlike most researchers, who have focused on the HIF-1 pathway for AKI protection and its enhancing glycolytic and metabolic effects on the tubular epithelium, this study concentrates on HIF-2 and the endothelium. Nangaku’s group already demonstrated that a lack of HIF-2a deteriorated ischemic injury in experimental AKI.7 Kidney International (2014) 85, 232–247
Thus targeting the endothelium for HIF-2a induction has interesting implications for present therapeutic approaches, using HIF-PHD inhibitors to protect kidneys from AKI. Originally, it was thought that the proximal tubule, with its low glycolytic capacity, can profit the most from pharmacological HIF induction. Unexpectedly, selective HIF induction in the proximal tubule had no protective effects in experimental AKI, whereas HIF induction in the thick ascending limb improved kidney function and structure.8 In comparison, HIF-2 in myeloid cells had no effects on LPS-mediated AKI protection, since bone marrow transplantation of HIF-2a-deficient cells to wild-type mice prior to ischemia–reperfusion experiments in the study by He et al.6 did not influence LPS-mediated protective effects—an experiment that became necessary because the Mx1 promoter also could delete HIF-2a in myeloid cells. Overall, these results strengthen the hypothesis that renoprotective LPS cross-tolerance primarily targets the kidney endothelium. These findings have potential implications for the use of systemic PHD inhibitors in AKI as well, which likewise protects the kidney and affects myeloid cells in parallel. A methodological limitation of the study is that conclusions about the role of endothelial cells in cross-tolerance were primarily based on cultured human umbilical vein endothelial cells. Thus, the definitive proof that HIF-2a is switched on primarily in endothelial cells in kidneys undergoing ischemia– reperfusion is somewhat incomplete, because appropriate immunohistochemistry data for HIF-2a are not presented. Indeed, HIF-2a was formerly termed endothelial PAS protein (EPAS1), since this HIF isoform was detected abundantly primarily in endothelial cells, but HIF-2a was later found in numerous other cells as well. In the kidney, HIF-2a expression is basically limited to interstitial fibroblasts and interstitial and glomerular endothelial cells. In the study by He et al.,6 HIF-2a accumulation in endothelial cells was
also linked to enhanced NO synthesis overall supporting the notion that endothelial cells present at least one target of LPS pretreatment. From a pathophysiological perspective, the present study has interesting implications for our understanding of microcirculatory changes and renal vasoconstriction in AKI. Indeed, a common hypothesis is that sepsis leads to vasoconstriction and inflammation, which aggravate ischemia and tubular injury. This concept for septic AKI has been challenged by several investigators, who have proposed renal vasodilatation and blood shunting in a septic state. The present study would support this notion, as LPS leads to HIF-2a-mediated enhanced NO synthesis with vasodilatory effects. A better understanding of circulatory effects in the kidney has therefore important implications for potential therapeutic approaches, since many studies focus on vasomodulating substances in clinical trials. Most experimental interventions that have demonstrated protective effects of HIF induction have been applied preconditionally prior to the ischemic injury. Unfortunately, in clinical practice, most patients will present after onset of AKI. In animal models, systemic PHD inhibition after ischemia– reperfusion has been shown to have no protective effects.9 The same may be true for LPS treatment. In fact, LPS treatment after ischemia–reperfusion of the kidney actually worsened outcomes,10 thus limiting direct translation of the observed effects into clinical practice. Nevertheless, the link between NF-kB and HIF may open an interesting new perspective that may facilitate the search for novel therapeutic options in AKI prevention and treatment. Furthermore, these considerations may also apply to other organs in which the phenomenon of cross-tolerance has been described. DISCLOSURE
The author declared no competing interests. REFERENCES 1.
Cramer T, Yamanishi Y, Clausen BE et al. HIF-1a is essential for myeloid cell-mediated inflammation. Cell 2003; 112: 645–657.
233
commentary
2.
3.
4.
5.
6.
Cummins EP, Berra E, Comerford KM et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 2006; 103: 18154–18159. Peyssonnaux C, Datta V, Cramer T et al. HIF-1a expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005; 115: 1806–1815. Heemann U, Szabo A, Hamar P et al. Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury: possible connection to an interleukin-6dependent pathway. Am J Pathol 2000; 156: 287–293. Zager RA, Johnson AC, Lund S. ‘Endotoxin tolerance’: TNF-alpha hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state. Kidney Int 2007; 71: 496–503. He K, Chen X, Han C et al. Lipopolysaccharideinduced cross-tolerance against renal ischemia–reperfusion injury is mediated
7.
8.
9.
10.
by hypoxia-inducible factor-2a-regulated nitric oxide production. Kidney Int 2014; 85: 276–288. Kojima I, Tanaka T, Inagi R et al. Protective role of hypoxia-inducible factor-2a against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 2007; 18: 1218–1226. Schley G, Klanke B, Schodel J et al. Selective stabilization of HIF-1a in renal tubular cells by 2-oxoglutarate analogues. Am J Pathol 2012; 181: 1595–1606. Wang Z, Schley G, Turkoglu G et al. The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol Dial Transplant 2012; 27: 929–936. Zager RA, Johnson AC, Hanson SY et al. Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-alpha generation and systemic release. Am J Physiol Renal Physiol 2005; 289: F289–F297.
see basic research on page 289
Myofibroblasts: the ideal target to prevent arteriovenous fistula failure? Juan Camilo Duque1 and Roberto I. Vazquez-Padron1 The arteriovenous fistula (AVF) failure is a major cause of morbidity in the hemodialysis population. Most AVFs fail due to neointimal hyperplasia (NIH). In this issue, Yang et al. delineated a mechanism responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. These authors pondered the role of hypoxia-regulated hypoxia-inducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of those adventitial myofibroblasts that may significantly contribute to the formation of the fistula neointima. Kidney International (2014) 85, 234–236. doi:10.1038/ki.2013.384
According to the US Renal Data System, 546,000 Americans rely on a vascular access to receive life-saving hemodialysis.1 The arteriovenous fistula (AVF) is the preferred vascular access 1 DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA Correspondence: Roberto I. Vazquez-Padron, Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, RMSB 1009D, Miami, Florida 33136, USA. E-mail: [email protected]
234
since the United States implemented the Fistula First Breakthrough Initiative in 2003, given its improved performance and lower complication rates compared with prosthetic grafts or central venous catheters. However, the rate of AVF failure (40–60%) is still unacceptable and profoundly impacts morbidity in the hemodialysis population. In general, AVF fails mostly because of complications secondary to obstructive neointimal hyperplasia (NIH). Despite the wide recognition of this problem, no
substantial efforts have been made so far to identify the underlying mechanisms that lead to the formation of occlusive neointima in AVF. The article by Yang et al.2 (this issue) contributes to the delineation of the cellular and molecular mechanisms responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. This and previous work from Dr. Misra’s group3 have highlighted the importance of hypoxiainducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of adventitial myofibroblasts that could potentially contribute to neointimal formation (Figure 1). Consequently, this study provides rationale for using anti-VEGF-A therapies at the time of fistula creation to avoid NIH and thus reduce the rate of primary failure in vascular accesses. Targeting myofibroblastic activity in the fistula adventitia at the time of creation to improve its maturation is an emerging idea that requires attention and further innovation. The myofibroblast is friend and foe during vein adaptation to arterial flow and is primordial to maintain venous hemostasis after AVF establishment.4 Myofibroblast precursors residing in the venous adventitia sense the abrupt mechanical forces produced by arterial flow to rapidly adjust its genomic expression program to help increase vascular resistance. This adaptive response includes the formation of bundles of contractile microfilaments and extensive cell-tomatrix attachment sites as well as the secretion of MMPs, collagen, and extracellular matrix proteins to re-enforce the fistula wall. However, the excessive myofibroblastic healing response typically observed after implementation of AVF contributes not only to neointimal formation but also to the thickening of the tunica media and adventitial fibrosis, which compromise the proper function of the fistula. As proposed by Yang et al.,2 an ideal therapy to reduce venous stenosis formation should be not only locally but also timely delivered to the adventitia of the vessel wall to prevent myofibroblast expansion while allowing Kidney International (2014) 85, 232–247
http://www.kidney-international.org & 2014 International Society of Nephrology
see basic research on page 276
HIF meets NF-jB signaling Carsten Willam1 An inflammatory stimulus prior to an ischemic insult can be protective in acute kidney injury (AKI) as well as other acute organ injury models, an effect called cross-tolerance. He et al. investigated mechanisms of cross-tolerance whereby pretreatment with lipopolysaccharide (LPS) protects from a subsequent ischemic insult of the kidney. The protection was mediated by LPS-induced nuclear factor-jB and hypoxia-inducible factor-2a (HIF-2a) signaling. These results link two central cellular pathways and give new insight into HIF-mediated renoprotection in AKI models. Kidney International (2014) 85, 232–234. doi:10.1038/ki.2013.362
Acute ischemia is traditionally thought to be the major pathophysiological event in the pathogenesis of rapidly deteriorating renal function in acute kidney injury (AKI). Ischemia evolves from an acute drop in oxygen supply, often due to low circulatory blood pressure. The kidney is presumably prone to severe ischemia, since, due to oxygen shunting and the postglomerular origin of the descending medullary microvessels, low oxygen tensions are already present in the medullary regions. However, ischemia not only represents simply a lack of energy substrates but is associated with a highly sophisticated regulatory oxygen sensing system in the kidney. This includes induction of more than 200 hypoxia-regulated genes, eventually, but not exclusively, leading to regulation of erythropoiesis and thus to improved oxygen transport throughout the body. The central regulators of this hypoxic response are the transcription factors hypoxia-inducible factors-1 and -2 (HIF-1 and -2) and a group of enzymes that control HIF protein levels, the HIF–prolyl hydroxylase domain enzymes 1 Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen, Germany Correspondence: Carsten Willam, Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. E-mail: [email protected]
232
1–3 (PHD1, -2, and -3), which have been identified as being highly expressed in the kidney. Promisingly, genetic or pharmacological stabilization of HIF, particularly in epithelial cells, impressively demonstrated protective effects in diverse models of experimental AKI. In addition to hypoxia, very convincing data demonstrate a major impact of inflammatory processes on the pathogenesis of ischemic AKI. Ischemic injuries are regularly linked with a marked inflammatory reaction, which leads to invasion of inflammatory cells and release of cytokines. This triggers a complex regulatory cascade that again compromises the homeostasis of the tubulointerstitium. In fact, new insights into inflammatory cascades demonstrated that the inflammatory and the hypoxic gene regulatory pathways may not be regarded as distinct pathophysiological events but are closely linked to each other. In 2003 Cramer et al. already showed that HIF-1a is essential for the inflammatory capacity of myeloid cells, because of the HIF-driven adaptation of glycolysis to metabolic needs. HIF-1 knockout led to a metabolic defect resulting in profound impairment of myeloid-cell aggregation, motility, invasiveness, and bacterial killing.1 Intriguingly, IkB kinase-b (IKKb), which phosphorylates the nuclear factor-kB (NF-kB) inhibitor IkB, is also regulated by the HIF-PHDs2 and
supported NF-kB signaling. Another important finding was that after bactericidal infection or lipopolysaccharide (LPS) exposure, HIF accumulated in inflammatory cells even in the presence of oxygen, implying a link between HIF stabilization and inflammatory NF-kB signaling mediated by Toll-like receptor-2 (TLR2) and TLR4.3 How the TLR-mediated NF-kB signaling translates into HIF stabilization in the presence of oxygen is still less clear. In the search for new molecular pathways to explore novel therapeutic options for protecting from AKI, it has been described that low-dose LPS pretreatment of mice protected from subsequent ischemic or toxic AKI or other organ damage respectively—a phenomenon called cross-tolerance.4,5 Now Kang He, Qiang Xia, and colleagues6 (this issue) demonstrate that LPS exposure prior to ischemia–reperfusion ameliorated AKI in mice (cross-tolerance) and give evidence for the linkage of LPSmediated NF-kB signaling and the HIF pathway in the kidney. Like in previous published studies, LPS pretreatment was protective in ischemia– reperfusion experiments. Importantly, LPS pretreatment led to enhanced HIF2a protein accumulation in kidney extracts. In experiments using Mx1 promoter-driven Cre-mediated conditional HIF knockout mice, only HIF-2a deficiency, not HIF-1a deficiency, abrogated LPS-induced renoprotection, indicating that HIF-2a was responsible for the observed effects. In experiments with human umbilical vein endothelial cells, LPS treatment induced HIF-2a in analogy to the experiments in vivo. This was abolished by the addition of an NF-kB nuclear translocation inhibitor. Hence the authors hypothesize that renoprotective LPS effects were mediated via NF-kB-induced HIF-2a stabilization in endothelial cells (Figure 1). In order to better understand transcriptional downstream effects of HIF-2 accumulation, mice were treated with inhibitors and donators of nitric oxide (NO), which showed that Kidney International (2014) 85, 232–247
commentary
LPS TLR NF-κB HIF-2 iNOS N O N O
Microcirculatory recovery
Figure 1 | Potential model of lipopolysaccharide-mediated crosstolerance in renal endothelial cells. Lipopolysaccharide (LPS) preconditioning induces nuclear factor-kB (NF-kB), which leads to endothelial HIF-2a accumulation. HIF-2a induces inducible nitric oxide synthase (iNOS), which enhances the nitric oxide (NO) level and improves microcirculatory effects in experimental ischemia–reperfusion. TLR, Toll-like receptor.
LPS pretreatment was protective only in the presence of NO in renal tissues. The authors eventually showed that re-establishment of the deteriorated NO synthesis after ischemia–reperfusion by LPS–HIF-2a signaling in the medulla was important for improved postischemic microcirculatory recovery, as assessed by laser Doppler flowmetry. Conversely, inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) expression was significantly reduced in HIF-2 knockout mice, suggesting that LPS effects were mediated via NF-kB-dependent HIF-2a-stimulated NOS expression. The study by He et al.6 can be regarded as a contribution to further unravel AKI pathophysiology and potential protective molecular pathways. Unlike most researchers, who have focused on the HIF-1 pathway for AKI protection and its enhancing glycolytic and metabolic effects on the tubular epithelium, this study concentrates on HIF-2 and the endothelium. Nangaku’s group already demonstrated that a lack of HIF-2a deteriorated ischemic injury in experimental AKI.7 Kidney International (2014) 85, 232–247
Thus targeting the endothelium for HIF-2a induction has interesting implications for present therapeutic approaches, using HIF-PHD inhibitors to protect kidneys from AKI. Originally, it was thought that the proximal tubule, with its low glycolytic capacity, can profit the most from pharmacological HIF induction. Unexpectedly, selective HIF induction in the proximal tubule had no protective effects in experimental AKI, whereas HIF induction in the thick ascending limb improved kidney function and structure.8 In comparison, HIF-2 in myeloid cells had no effects on LPS-mediated AKI protection, since bone marrow transplantation of HIF-2a-deficient cells to wild-type mice prior to ischemia–reperfusion experiments in the study by He et al.6 did not influence LPS-mediated protective effects—an experiment that became necessary because the Mx1 promoter also could delete HIF-2a in myeloid cells. Overall, these results strengthen the hypothesis that renoprotective LPS cross-tolerance primarily targets the kidney endothelium. These findings have potential implications for the use of systemic PHD inhibitors in AKI as well, which likewise protects the kidney and affects myeloid cells in parallel. A methodological limitation of the study is that conclusions about the role of endothelial cells in cross-tolerance were primarily based on cultured human umbilical vein endothelial cells. Thus, the definitive proof that HIF-2a is switched on primarily in endothelial cells in kidneys undergoing ischemia– reperfusion is somewhat incomplete, because appropriate immunohistochemistry data for HIF-2a are not presented. Indeed, HIF-2a was formerly termed endothelial PAS protein (EPAS1), since this HIF isoform was detected abundantly primarily in endothelial cells, but HIF-2a was later found in numerous other cells as well. In the kidney, HIF-2a expression is basically limited to interstitial fibroblasts and interstitial and glomerular endothelial cells. In the study by He et al.,6 HIF-2a accumulation in endothelial cells was
also linked to enhanced NO synthesis overall supporting the notion that endothelial cells present at least one target of LPS pretreatment. From a pathophysiological perspective, the present study has interesting implications for our understanding of microcirculatory changes and renal vasoconstriction in AKI. Indeed, a common hypothesis is that sepsis leads to vasoconstriction and inflammation, which aggravate ischemia and tubular injury. This concept for septic AKI has been challenged by several investigators, who have proposed renal vasodilatation and blood shunting in a septic state. The present study would support this notion, as LPS leads to HIF-2a-mediated enhanced NO synthesis with vasodilatory effects. A better understanding of circulatory effects in the kidney has therefore important implications for potential therapeutic approaches, since many studies focus on vasomodulating substances in clinical trials. Most experimental interventions that have demonstrated protective effects of HIF induction have been applied preconditionally prior to the ischemic injury. Unfortunately, in clinical practice, most patients will present after onset of AKI. In animal models, systemic PHD inhibition after ischemia– reperfusion has been shown to have no protective effects.9 The same may be true for LPS treatment. In fact, LPS treatment after ischemia–reperfusion of the kidney actually worsened outcomes,10 thus limiting direct translation of the observed effects into clinical practice. Nevertheless, the link between NF-kB and HIF may open an interesting new perspective that may facilitate the search for novel therapeutic options in AKI prevention and treatment. Furthermore, these considerations may also apply to other organs in which the phenomenon of cross-tolerance has been described. DISCLOSURE
The author declared no competing interests. REFERENCES 1.
Cramer T, Yamanishi Y, Clausen BE et al. HIF-1a is essential for myeloid cell-mediated inflammation. Cell 2003; 112: 645–657.
233
commentary
2.
3.
4.
5.
6.
Cummins EP, Berra E, Comerford KM et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 2006; 103: 18154–18159. Peyssonnaux C, Datta V, Cramer T et al. HIF-1a expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005; 115: 1806–1815. Heemann U, Szabo A, Hamar P et al. Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury: possible connection to an interleukin-6dependent pathway. Am J Pathol 2000; 156: 287–293. Zager RA, Johnson AC, Lund S. ‘Endotoxin tolerance’: TNF-alpha hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state. Kidney Int 2007; 71: 496–503. He K, Chen X, Han C et al. Lipopolysaccharideinduced cross-tolerance against renal ischemia–reperfusion injury is mediated
7.
8.
9.
10.
by hypoxia-inducible factor-2a-regulated nitric oxide production. Kidney Int 2014; 85: 276–288. Kojima I, Tanaka T, Inagi R et al. Protective role of hypoxia-inducible factor-2a against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 2007; 18: 1218–1226. Schley G, Klanke B, Schodel J et al. Selective stabilization of HIF-1a in renal tubular cells by 2-oxoglutarate analogues. Am J Pathol 2012; 181: 1595–1606. Wang Z, Schley G, Turkoglu G et al. The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol Dial Transplant 2012; 27: 929–936. Zager RA, Johnson AC, Hanson SY et al. Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-alpha generation and systemic release. Am J Physiol Renal Physiol 2005; 289: F289–F297.
see basic research on page 289
Myofibroblasts: the ideal target to prevent arteriovenous fistula failure? Juan Camilo Duque1 and Roberto I. Vazquez-Padron1 The arteriovenous fistula (AVF) failure is a major cause of morbidity in the hemodialysis population. Most AVFs fail due to neointimal hyperplasia (NIH). In this issue, Yang et al. delineated a mechanism responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. These authors pondered the role of hypoxia-regulated hypoxia-inducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of those adventitial myofibroblasts that may significantly contribute to the formation of the fistula neointima. Kidney International (2014) 85, 234–236. doi:10.1038/ki.2013.384
According to the US Renal Data System, 546,000 Americans rely on a vascular access to receive life-saving hemodialysis.1 The arteriovenous fistula (AVF) is the preferred vascular access 1 DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA Correspondence: Roberto I. Vazquez-Padron, Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, RMSB 1009D, Miami, Florida 33136, USA. E-mail: [email protected]
234
since the United States implemented the Fistula First Breakthrough Initiative in 2003, given its improved performance and lower complication rates compared with prosthetic grafts or central venous catheters. However, the rate of AVF failure (40–60%) is still unacceptable and profoundly impacts morbidity in the hemodialysis population. In general, AVF fails mostly because of complications secondary to obstructive neointimal hyperplasia (NIH). Despite the wide recognition of this problem, no
substantial efforts have been made so far to identify the underlying mechanisms that lead to the formation of occlusive neointima in AVF. The article by Yang et al.2 (this issue) contributes to the delineation of the cellular and molecular mechanisms responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. This and previous work from Dr. Misra’s group3 have highlighted the importance of hypoxiainducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of adventitial myofibroblasts that could potentially contribute to neointimal formation (Figure 1). Consequently, this study provides rationale for using anti-VEGF-A therapies at the time of fistula creation to avoid NIH and thus reduce the rate of primary failure in vascular accesses. Targeting myofibroblastic activity in the fistula adventitia at the time of creation to improve its maturation is an emerging idea that requires attention and further innovation. The myofibroblast is friend and foe during vein adaptation to arterial flow and is primordial to maintain venous hemostasis after AVF establishment.4 Myofibroblast precursors residing in the venous adventitia sense the abrupt mechanical forces produced by arterial flow to rapidly adjust its genomic expression program to help increase vascular resistance. This adaptive response includes the formation of bundles of contractile microfilaments and extensive cell-tomatrix attachment sites as well as the secretion of MMPs, collagen, and extracellular matrix proteins to re-enforce the fistula wall. However, the excessive myofibroblastic healing response typically observed after implementation of AVF contributes not only to neointimal formation but also to the thickening of the tunica media and adventitial fibrosis, which compromise the proper function of the fistula. As proposed by Yang et al.,2 an ideal therapy to reduce venous stenosis formation should be not only locally but also timely delivered to the adventitia of the vessel wall to prevent myofibroblast expansion while allowing Kidney International (2014) 85, 232–247
