急性肾损伤肾小管上皮细胞修复的分子机制
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摘要
近端小管上皮细胞凋亡或坏死是急性肾损伤(AKI)最常见的原因。各种损伤可诱导激活上皮细胞关键转录因子和上皮内再生因子,促进肾小管上皮细胞-间充质转化。肾小管上皮细胞与免疫细胞、间质细胞和内皮细胞之间复杂的分子交互作用可调节肾脏的修复。与公认的促炎、促纤维化机制不同,越来越多的研究表明存在促进损伤后肾脏修复的巨噬细胞、T细胞、B细胞亚群。在轻中度急性肾单位损伤区域,受损的肾小管上皮细胞可完全再生修复。重度损伤区域,再生过程受损失调,引起广泛的组织重塑和纤维化。
The most common cause of acute kidney injury(AKI) is apoptosis or necrosis of proximal tubular epithelial cells.Injury induces activation of key developmental transcription factors,activates the intrinsic molecular driver of epithelial regeneration,and promotes nephron epithelial-mesenchymal transition.Complex molecular interactions between renal tubular epithelial cells and immune,interstitial and endothelial cells regulate renal repair.Unlike the commonly recognized proinflammatory and profibrotic effects,more and more studies have indicated the presence of macrophages,T-cell,and B-cell subtypes that promote renal recovery after injury.Regions of mild to moderate acute nephron injury,the injured nephron epithelial cells regenerate and completely repair to the previous morphology.In areas with severe injury,the regeneration process is subject to loss,resulting in extensive tissue remodeling and fibrosis.
The most common cause of acute kidney injury(AKI) is apoptosis or necrosis of proximal tubular epithelial cells.Injury induces activation of key developmental transcription factors,activates the intrinsic molecular driver of epithelial regeneration,and promotes nephron epithelial-mesenchymal transition.Complex molecular interactions between renal tubular epithelial cells and immune,interstitial and endothelial cells regulate renal repair.Unlike the commonly recognized proinflammatory and profibrotic effects,more and more studies have indicated the presence of macrophages,T-cell,and B-cell subtypes that promote renal recovery after injury.Regions of mild to moderate acute nephron injury,the injured nephron epithelial cells regenerate and completely repair to the previous morphology.In areas with severe injury,the regeneration process is subject to loss,resulting in extensive tissue remodeling and fibrosis.
引文
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2 Venkatachalam MA,Weinberg JM,Kriz W,et al.Failed Tubule Recovery,AKI-CKD Transition,and Kidney Disease Progression.J Am Soc Nephrol,2015,26(8):1765-1776.
3 Duffield JS,Park KM,Hsiao LL,et al.Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells.J Clin Invest,2005,115(7):1743-1755.
4 Kusaba T,Humphreys BD.Controversies on the origin of proliferating epithelial cells after kidney injury.Pediatr Nephrol,2014,29(4):673-679.
5 Sagrinati C,Netti GS,Mazzinghi B,et al.Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys.J Am Soc Nephrol,2006,17(9):2443-2456.
6 Guimar?es-Camboa N,Cattaneo P,Sun Y,et al.Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo.Cell Stem Cell,2017,20(3):345-359.e5.
7 Corbeil D,Fargeas CA,Jászai J.CD133 might be a pan marker of epithelial cells with dedifferentiation capacity.Proc Natl Acad Sci U S A,2014,111(15):E1451-1452.
8 Lindgren D,Bostr?m AK,Nilsson K,et al.Isolation and characterization of progenitor-like cells from human renal proximal tubules.Am J Pathol,2011,178(2):828-837.
9 Kusaba T,Lalli M,Kramann R,et al.Differentiated kidney epithelial cells repair injured proximal tubule.Proc Natl Acad Sci U S A,2014,111(4):1527-1532.
10 Appel D,Kershaw DB,Smeets B,et al.Recruitment of podocytes from glomerular parietal epithelial cells.J Am Soc Nephrol,2009,20(2):333-343.
11 Rinkevich Y,Montoro DT,Contreras-Trujillo H,et al.In vivo clonal analysis reveals lineage-restricted progenitor characteristics in mammalian kidney development,maintenance,and regeneration.Cell Rep,2014,7(4):1270-1283.
12 Terada Y,Tanaka H,Okado T,et al.Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats.J Am Soc Nephrol,2003,14(5):1223-1233.
13 DiRocco DP,Kobayashi A,Taketo MM,et al.Wnt4/β-catenin signaling in medullary kidney myofibroblasts.J Am Soc Nephrol,2013,24(9):1399-1412.
14 Kumar S,Liu J,Pang P,et al.Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney.Cell Rep,2015,12(8):1325-1338.
15 Liu J,Krautzberger AM,Sui SH,et al.Cell-specific translational profiling in acute kidney injury.J Clin Invest,2014,124(3):1242-1254.
16 Kang HM,Huang S,Reidy K,et al.Sox9-Positive Progenitor Cells Play a Key Role in Renal Tubule Epithelial Regeneration in Mice.Cell Rep,2016,14(4):861-871.
17 Wagner T,Wirth J,Meyer J,et al.Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.Cell,1994,79(6):1111-1120.
18 Reginensi A,Clarkson M,Neirijnck Y,et al.SOX9 controls epithelial branching by activating RET effector genes during kidney development.Hum Mol Genet,2011,20(6):1143-1153.
19 Kumar S,Liu J,McMahon AP.Defining the acute kidney injury and repair transcriptome.Semin Nephrol,2014,34(4):404-417.
20 Imgrund M,Gr?ne E,Gr?ne HJ,et al.Re-expression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice 1.Kidney Int,1999,56(4):1423-1431.
21 Rosen S,Heyman S.Concerning cellular and molecular pathways of renal repair after acute kidney injury.Kidney Int,2018,94(1):218.
22 Lovisa S,LeBleu VS,Tampe B,et al.Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis.Nat Med,2015,21(9):998-1009.
23 Grande MT,Sánchez-Laorden B,López-Blau C,et al.Erratum: Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease.Nat Med,2016,22(2):217.
24 Yang L,Besschetnova TY,Brooks CR,et al.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med,2010,16(5):535-543,1p following 143.
25 Humphreys BD,Lin SL,Kobayashi A,et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol,2010,176(1):85-97.
26 Chen J,Chen JK,Harris RC.Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury.Kidney Int,2012,82(1):45-52.
27 Sakai M,Zhang M,Homma T,et al.Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury.Isolation and localization of bioactive molecules.J Clin Invest,1997,99(9):2128-2138.
28 Chen J,Chen JK,Conway EM,et al.Survivin mediates renal proximal tubule recovery from AKI.J Am Soc Nephrol,2013,24(12):2023-2033.
2 Venkatachalam MA,Weinberg JM,Kriz W,et al.Failed Tubule Recovery,AKI-CKD Transition,and Kidney Disease Progression.J Am Soc Nephrol,2015,26(8):1765-1776.
3 Duffield JS,Park KM,Hsiao LL,et al.Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells.J Clin Invest,2005,115(7):1743-1755.
4 Kusaba T,Humphreys BD.Controversies on the origin of proliferating epithelial cells after kidney injury.Pediatr Nephrol,2014,29(4):673-679.
5 Sagrinati C,Netti GS,Mazzinghi B,et al.Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys.J Am Soc Nephrol,2006,17(9):2443-2456.
6 Guimar?es-Camboa N,Cattaneo P,Sun Y,et al.Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo.Cell Stem Cell,2017,20(3):345-359.e5.
7 Corbeil D,Fargeas CA,Jászai J.CD133 might be a pan marker of epithelial cells with dedifferentiation capacity.Proc Natl Acad Sci U S A,2014,111(15):E1451-1452.
8 Lindgren D,Bostr?m AK,Nilsson K,et al.Isolation and characterization of progenitor-like cells from human renal proximal tubules.Am J Pathol,2011,178(2):828-837.
9 Kusaba T,Lalli M,Kramann R,et al.Differentiated kidney epithelial cells repair injured proximal tubule.Proc Natl Acad Sci U S A,2014,111(4):1527-1532.
10 Appel D,Kershaw DB,Smeets B,et al.Recruitment of podocytes from glomerular parietal epithelial cells.J Am Soc Nephrol,2009,20(2):333-343.
11 Rinkevich Y,Montoro DT,Contreras-Trujillo H,et al.In vivo clonal analysis reveals lineage-restricted progenitor characteristics in mammalian kidney development,maintenance,and regeneration.Cell Rep,2014,7(4):1270-1283.
12 Terada Y,Tanaka H,Okado T,et al.Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats.J Am Soc Nephrol,2003,14(5):1223-1233.
13 DiRocco DP,Kobayashi A,Taketo MM,et al.Wnt4/β-catenin signaling in medullary kidney myofibroblasts.J Am Soc Nephrol,2013,24(9):1399-1412.
14 Kumar S,Liu J,Pang P,et al.Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney.Cell Rep,2015,12(8):1325-1338.
15 Liu J,Krautzberger AM,Sui SH,et al.Cell-specific translational profiling in acute kidney injury.J Clin Invest,2014,124(3):1242-1254.
16 Kang HM,Huang S,Reidy K,et al.Sox9-Positive Progenitor Cells Play a Key Role in Renal Tubule Epithelial Regeneration in Mice.Cell Rep,2016,14(4):861-871.
17 Wagner T,Wirth J,Meyer J,et al.Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.Cell,1994,79(6):1111-1120.
18 Reginensi A,Clarkson M,Neirijnck Y,et al.SOX9 controls epithelial branching by activating RET effector genes during kidney development.Hum Mol Genet,2011,20(6):1143-1153.
19 Kumar S,Liu J,McMahon AP.Defining the acute kidney injury and repair transcriptome.Semin Nephrol,2014,34(4):404-417.
20 Imgrund M,Gr?ne E,Gr?ne HJ,et al.Re-expression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice 1.Kidney Int,1999,56(4):1423-1431.
21 Rosen S,Heyman S.Concerning cellular and molecular pathways of renal repair after acute kidney injury.Kidney Int,2018,94(1):218.
22 Lovisa S,LeBleu VS,Tampe B,et al.Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis.Nat Med,2015,21(9):998-1009.
23 Grande MT,Sánchez-Laorden B,López-Blau C,et al.Erratum: Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease.Nat Med,2016,22(2):217.
24 Yang L,Besschetnova TY,Brooks CR,et al.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med,2010,16(5):535-543,1p following 143.
25 Humphreys BD,Lin SL,Kobayashi A,et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol,2010,176(1):85-97.
26 Chen J,Chen JK,Harris RC.Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury.Kidney Int,2012,82(1):45-52.
27 Sakai M,Zhang M,Homma T,et al.Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury.Isolation and localization of bioactive molecules.J Clin Invest,1997,99(9):2128-2138.
28 Chen J,Chen JK,Conway EM,et al.Survivin mediates renal proximal tubule recovery from AKI.J Am Soc Nephrol,2013,24(12):2023-2033.