Renal tubule injury: a driving force toward chronic kidney disease

Renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and senescence. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney diseases. In response to injury, tubular epithelial cells undergo changes and function as inflammatory and fibrogenic cells, with the consequent production of various bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the tubular epithelium also aggravate immune responses. Necroinflammation, an autoamplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, tubular cells also play an active role in progressive renal injury via emerging mechanisms associated with a partial epithelial-mesenchymal transition, cell-cycle arrest at both G1/S and G2/M check points, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives inflammation and fibrosis is necessary for the development of therapeutics to halt the progression of chronic kidney disease. Renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and senescence. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney diseases. In response to injury, tubular epithelial cells undergo changes and function as inflammatory and fibrogenic cells, with the consequent production of various bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the tubular epithelium also aggravate immune responses. Necroinflammation, an autoamplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, tubular cells also play an active role in progressive renal injury via emerging mechanisms associated with a partial epithelial-mesenchymal transition, cell-cycle arrest at both G1/S and G2/M check points, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives inflammation and fibrosis is necessary for the development of therapeutics to halt the progression of chronic kidney disease. The renal tubules and tubulointerstitium make up a significant portion of the kidney and are the major sites in response to injuries. Increasing evidence shows that tubular epithelial cells (TECs) play diverse roles in renal repair or progression to chronic kidney disease (CKD). The innate immune characteristics of TECs enable them to act as immune responders to a wide range of insults, with the consequent production and release of bioactive mediators that drive interstitial inflammation and fibrosis. Accumulating evidence shows that renal function decline correlates better with tubulointerstitial damage than that of glomerular injury.1Risdon R.A. Sloper J.C. De Wardener H.E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis.Lancet. 1968; 2: 363-366Abstract PubMed Google Scholar, 2Bohle A. Christ H. Grund K.E. Mackensen S. 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Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression.J Am Soc Nephrol. 2015; 26: 1765-1776Crossref PubMed Scopus (94) Google Scholar Thus, TECs should be regarded not only as victims in the context of kidney diseases, but also as key inflammatory and fibrogenic cells that drive the progression from acute to chronic kidney disease. It should be noted that due to the length limitations, this review focuses on the emerging mechanisms by which TECs play a driving role in renal injury, whereas other potentially important factors/pathways not directly related to this topic are not discussed here. Researches have shown that tubulointerstitial inflammation can be observed in the early stage of many renal diseases,6Lv L.L. Tang P.M. Li C.J. et al.The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation.Kidney Int. 2017; 91: 587-602Abstract Full Text Full Text PDF PubMed Google Scholar and the response of TECs to injury is likely to be a key determinant in the development of interstitial inflammation. These damaged TECs can be transformed into a secretory phenotype and elicit proinflammatory mediators. Injured TECs can facilitate the immune response through induction of a variety of proinflammatory cytokines (e.g., interleukin, tumor necrosis factor, colony-stimulating factor, and growth factor). After the first report of tumor necrosis factor (TNF)-α and interleukin (IL)-6 produced by TECs.7Jevnikar A.M. Brennan D.C. Singer G.G. Heng J.E. et al.Stimulated kidney tubular epithelial cells express membrane associated and secreted TNF alpha.Kidney Int. 1991; 40: 203-211Abstract Full Text PDF PubMed Google Scholar, 8Yard B.A. Daha M.R. Kooymans-Couthino M. et al.IL-1 alpha stimulated TNF alpha production by cultured human proximal tubular epithelial cells.Kidney Int. 1992; 42: 383-389Abstract Full Text PDF PubMed Google Scholar As shown in Table 1, a variety of cytokines have been shown to be produced by activated TECs, including IL-1β,9Leeans J.C. Kors L. Anders H.J. Florquin S. Pattern recognition receptors and the inflammasome in kidney disease.Nat Rev Nephrol. 2014; 10: 398-414Crossref PubMed Scopus (38) Google Scholar, 10Anders H.J. Of inflammasomes and alarmins: IL-1β and IL-1α in kidney disease.J Am Soc Nephrol. 2016; 27: 2564-2575Crossref PubMed Scopus (77) Google Scholar IL-18,9Leeans J.C. Kors L. Anders H.J. Florquin S. Pattern recognition receptors and the inflammasome in kidney disease.Nat Rev Nephrol. 2014; 10: 398-414Crossref PubMed Scopus (38) Google Scholar, 11Yang Y. Zhang Z.X. Lian D. et al.IL-37 inhibits IL-18-induced tubular epithelial cell expression of pro-inflammatory cytokines and renal ischemia-reperfusion injury.Kidney Int. 2015; 87: 396-408Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar IL-15,12Wong W.K. Robertson H. Carroll H.P. et al.Tubulitis in renal allograft rejection: role of transforming growth factor-beta and interleukin-15 in development and maintenance of CD103+ intraepithelial T cells.Transplantation. 2003; 75: 505-514Crossref PubMed Scopus (0) Google Scholar, 13Weiler M. Kachko L. Chaimovitz C. et al.CD40 ligation enhances IL-15 production by tubular epithelial cells.J Am Soc Nephrol. 2001; 12: 80-87PubMed Google Scholar IL-16,14Wang S. Diao H. Guan Q. et al.Decreased renal ischemia-reperfusion injury by IL-16 inactivation.Kidney Int. 2008; 73: 318-326Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar TNF-α,15Al-Lamki R.S. Mayadas T.N. TNF receptors: signaling pathways and contribution to renal dysfunction.Kidney Int. 2015; 87: 281-296Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar TWEAK,16Sanz A.B. Izquierdo M.C. Sanchez-Niño M.D. et al.TWEAK and the progression of renal disease: clinical translation.Nephrol Dial Transplant. 2014; 29: i54-i62Crossref PubMed Scopus (0) Google Scholar, 17Sanz A.B. Sanchez-Niño M.D. Ortiz A. TWEAK, a multifunctional cytokine in kidney injury.Kidney Int. 2011; 80: 708-718Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Fas ligand,18Ortiz A. Lorz C. Egido J. The Fas ligand/Fas system in renal injury.Nephrol Dial Transplant. 1999; 14: 1831-1834Crossref PubMed Scopus (0) Google Scholar, 19Lorz C. Ortiz A. Justo P. et al.Proapoptotic Fas ligand is expressed by normal kidney tubular epithelium and injured glomeruli.J Am Soc Nephrol. 2000; 11: 1266-1277Crossref PubMed Google Scholar connective tissue growth factor (CTGF),20Sánchez-López E. Rayego S. Rodrigues-Díez R. et al.CTGF promotes inflammatory cell infiltration of the renal interstitium by activating NF-kappaB.J Am Soc Nephrol. 2009; 20: 1513-1526Crossref PubMed Scopus (68) Google Scholar, 21Rodrigues-Diez R.R. Garcia-Redondo A.B. Orejudo M. et al.The C-terminal module IV of connective tissue growth factor, through EGFR/Nox1 signaling, activates the NF-κB pathway and proinflammatory factors in vascular smooth muscle cells.Antioxid Redox Signal. 2015; 22: 29-47Crossref PubMed Scopus (9) Google Scholar and vascular endothelial growth factor.22Ninichuk V. Gross O. Segerer S. et al.Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice.Kidney Int. 2006; 70: 121-129Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 23Kang D.H. Joly A.H. Oh S.W. et al.Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1.J Am Soc Nephrol. 2001; 12: 1434-1447Crossref PubMed Google Scholar, 24Schrijvers B.F. Flyvbjerg A. Tilton R.G. et al.Pathophysiological role of vascular endothelial growth factor in the remnant kidney.Nephron Exp Nephrol. 2005; 101: e9-e15Crossref PubMed Scopus (0) Google Scholar Recently, emerging evidence indicates that the expression of colony-stimulating factor 1 is upregulated in TECs and may be responsible for the polarization of renal macrophages and recovery from AKI.25Menke J. Iwata Y. Rabacal W.A. et al.CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice.J Clin Invest. 2009; 119: 2330-2342Crossref PubMed Scopus (97) Google Scholar, 26Wang Y. Chang J. Yao B. et al.Proximal tubule-derived colony stimulating factor-1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury.Kidney Int. 2015; 88: 1274-1282Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 27Huen S.C. Huynh L. Marlier A. et al.GM-CSF Promotes Macrophage Alternative Activation after Renal Ischemia/Reperfusion Injury.J Am Soc Nephrol. 2015; 26: 1334-1345Crossref PubMed Scopus (25) Google Scholar TEC-derived IL-34 also plays a key role in aggravating macrophage infiltration and tubular cell injury, leading to persistent ischemic AKI and subsequent CKD.28Baek J.H. Zeng R. Weinmann-Menke J. et al.IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease.J Clin Invest. 2015; 125: 3198-3214Crossref PubMed Scopus (92) Google Scholar These findings support the notion that activated TECs gain the inflammatory phenotype that drives the immune response by producing inflammatory cytokines directly in an autocrine manner or indirectly through the infiltrating leukocytes in a paracrine manner.Table 1List of proinflammatory cytokines produced by TECsCytokinesEffectsReferencesIL-1βTriggers proinflammatory cytokines and initiates acute-phase responses9Leeans J.C. Kors L. Anders H.J. Florquin S. Pattern recognition receptors and the inflammasome in kidney disease.Nat Rev Nephrol. 2014; 10: 398-414Crossref PubMed Scopus (38) Google Scholar, 10Anders H.J. Of inflammasomes and alarmins: IL-1β and IL-1α in kidney disease.J Am Soc Nephrol. 2016; 27: 2564-2575Crossref PubMed Scopus (77) Google ScholarIL-18Triggers proinflammatory cytokines9Leeans J.C. Kors L. Anders H.J. Florquin S. Pattern recognition receptors and the inflammasome in kidney disease.Nat Rev Nephrol. 2014; 10: 398-414Crossref PubMed Scopus (38) Google Scholar, 11Yang Y. Zhang Z.X. Lian D. et al.IL-37 inhibits IL-18-induced tubular epithelial cell expression of pro-inflammatory cytokines and renal ischemia-reperfusion injury.Kidney Int. 2015; 87: 396-408Abstract Full Text Full Text PDF PubMed Scopus (29) Google ScholarIL-6Proinflammation7Jevnikar A.M. Brennan D.C. Singer G.G. Heng J.E. et al.Stimulated kidney tubular epithelial cells express membrane associated and secreted TNF alpha.Kidney Int. 1991; 40: 203-211Abstract Full Text PDF PubMed Google Scholar, 8Yard B.A. Daha M.R. Kooymans-Couthino M. et al.IL-1 alpha stimulated TNF alpha production by cultured human proximal tubular epithelial cells.Kidney Int. 1992; 42: 383-389Abstract Full Text PDF PubMed Google ScholarIL-15CD103+ T-cell recruitment12Wong W.K. Robertson H. Carroll H.P. et al.Tubulitis in renal allograft rejection: role of transforming growth factor-beta and interleukin-15 in development and maintenance of CD103+ intraepithelial T cells.Transplantation. 2003; 75: 505-514Crossref PubMed Scopus (0) Google Scholar, 13Weiler M. Kachko L. Chaimovitz C. et al.CD40 ligation enhances IL-15 production by tubular epithelial cells.J Am Soc Nephrol. 2001; 12: 80-87PubMed Google ScholarIL-16CD4+ T-cell recruitment14Wang S. Diao H. Guan Q. et al.Decreased renal ischemia-reperfusion injury by IL-16 inactivation.Kidney Int. 2008; 73: 318-326Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarIL-34Neutrophil and macrophage recruitment28Baek J.H. Zeng R. Weinmann-Menke J. et al.IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease.J Clin Invest. 2015; 125: 3198-3214Crossref PubMed Scopus (92) Google ScholarTNF-αTriggers proinflammatory cytokinesInnate and adaptive immunityApoptosis15Al-Lamki R.S. Mayadas T.N. TNF receptors: signaling pathways and contribution to renal dysfunction.Kidney Int. 2015; 87: 281-296Abstract Full Text Full Text PDF PubMed Scopus (34) Google ScholarCSF-1Macrophage recruitment and adhesionPolarization into an M2 phenotype25Menke J. Iwata Y. Rabacal W.A. et al.CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice.J Clin Invest. 2009; 119: 2330-2342Crossref PubMed Scopus (97) Google Scholar, 26Wang Y. Chang J. Yao B. et al.Proximal tubule-derived colony stimulating factor-1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury.Kidney Int. 2015; 88: 1274-1282Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 27Huen S.C. Huynh L. Marlier A. et al.GM-CSF Promotes Macrophage Alternative Activation after Renal Ischemia/Reperfusion Injury.J Am Soc Nephrol. 2015; 26: 1334-1345Crossref PubMed Scopus (25) Google ScholarTWEAKCell death in the presence of TNF-α/IFN-γProinflammation16Sanz A.B. Izquierdo M.C. Sanchez-Niño M.D. et al.TWEAK and the progression of renal disease: clinical translation.Nephrol Dial Transplant. 2014; 29: i54-i62Crossref PubMed Scopus (0) Google Scholar, 17Sanz A.B. Sanchez-Niño M.D. Ortiz A. TWEAK, a multifunctional cytokine in kidney injury.Kidney Int. 2011; 80: 708-718Abstract Full Text Full Text PDF PubMed Scopus (51) Google ScholarFas ligandApoptosis18Ortiz A. Lorz C. Egido J. The Fas ligand/Fas system in renal injury.Nephrol Dial Transplant. 1999; 14: 1831-1834Crossref PubMed Scopus (0) Google Scholar, 19Lorz C. Ortiz A. Justo P. et al.Proapoptotic Fas ligand is expressed by normal kidney tubular epithelium and injured glomeruli.J Am Soc Nephrol. 2000; 11: 1266-1277Crossref PubMed Google ScholarCTGFTriggers proinflammatory cytokines20Sánchez-López E. Rayego S. Rodrigues-Díez R. et al.CTGF promotes inflammatory cell infiltration of the renal interstitium by activating NF-kappaB.J Am Soc Nephrol. 2009; 20: 1513-1526Crossref PubMed Scopus (68) Google Scholar, 21Rodrigues-Diez R.R. Garcia-Redondo A.B. Orejudo M. et al.The C-terminal module IV of connective tissue growth factor, through EGFR/Nox1 signaling, activates the NF-κB pathway and proinflammatory factors in vascular smooth muscle cells.Antioxid Redox Signal. 2015; 22: 29-47Crossref PubMed Scopus (9) Google ScholarVEGFMacrophage recruitment22Ninichuk V. Gross O. Segerer S. et al.Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice.Kidney Int. 2006; 70: 121-129Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 23Kang D.H. Joly A.H. Oh S.W. et al.Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1.J Am Soc Nephrol. 2001; 12: 1434-1447Crossref PubMed Google Scholar, 24Schrijvers B.F. Flyvbjerg A. Tilton R.G. et al.Pathophysiological role of vascular endothelial growth factor in the remnant kidney.Nephron Exp Nephrol. 2005; 101: e9-e15Crossref PubMed Scopus (0) Google ScholarCSF-1, colony-stimulating factor 1; CTGF, connective tissue growth factor; IL, interleukin; TECs, tubular epithelial cells; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor. Open table in a new tab CSF-1, colony-stimulating factor 1; CTGF, connective tissue growth factor; IL, interleukin; TECs, tubular epithelial cells; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor. Chemokines are a family of small molecular cytokines with chemotactic activity. TECs are rich sources of the CC chemokine ligand (CCL) subfamily including monocyte chemoattractant protein-1/CCL2, RANTES (regulated on activation, T-cell expressed, and secreted)/CCL5, and monocyte chemoattractant protein-1/CCL3, and CX3CL subfamily (fractalkine/CX3CL1).29Chung A.C. Lan H.Y. Chemokines in renal injury.J Am Soc Nephrol. 2011; 22: 802-809Crossref PubMed Scopus (94) Google Scholar Monocyte chemoattractant protein-1/CCL2 is one of the most widely studied chemokines in kidney injury.30Wang Y. Chen J. 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Ding L.H. et al.Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: a novel mechanism of albumin-induced tubulointerstitial inflammation.Int J Biochem Cell Biol. 2014; 57: 7-19Crossref PubMed Scopus (29) Google Scholar Taken together, a surplus of ROS in TECs can result in various injurious consequences such as inflammation. C-reactive protein (CRP) is an acute-phase protein that is rapidly synthesized by the liver in response to infection, inflammation, and tissue damage. Besides its use as a biomarker of inflammation, CRP has been recognized as a pathogenic mediator in diabetic kidney disease,55Liu F. Chen H.Y. Huang X.R. et al.C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes.Diabetologia. 2011; 54: 2713-2723Crossref PubMed Scopus (30) Google Scholar obstructive nephropathy,56Li Z.I. Chung A.C. 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Huang X.R. et al.C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E.Kidney Int. 2016; 90: 610-626Abstract Full Text Full Text PDF PubMed Google Scholar CRP is also inducible by high glucose in human TECs and promotes renal inflammation and fibrosis through activation of TGF-β/Smad and NF-κB signaling pathways under diabetic conditions and unilateral ureteral obstructive nephropathy.55Liu F. Chen H.Y. Huang X.R. et al.C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes.Diabetologia. 2011; 54: 2713-2723Crossref PubMed Scopus (30) Google Scholar, 56Li Z.I. Chung A.C. Zhou L. et al.C-reactive protein promotes acute renal inflammation and fibrosis in unilateral ureteral obstructive nephropathy in mice.Lab Invest. 2011; 91: 837-851Crossref PubMed Scopus (25) Google Scholar Recent studies demonstrated that CRP promotes AKI by causing TEC G1 cell-cycle arrest via CD32-Smad3–dependent p27-driven inhibition of the cyclin-dependent kinase 2/cyclin E mechanism.58Tang Y. Huang X.R. Lv J. et al.C-reactive protein promotes acute kidney injury by impairing G1/S-dependent tubular epithelium cell regeneration.Clin Sci (Lond). 2014; 126: 645-659Crossref PubMed Scopus (18) Google Scholar, 59Lai W. Tang Y. Huang X.R. et al.C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E.Kidney Int. 2016; 90: 610-626Abstract Full Text Full Text PDF PubMed Google Scholar TECs often localize at the epicenter of kidney injury and are especially vulnerable to damage. After severe or recurrent injury, TECs undergo changes in structure and phenotype that are accompanied by altered expression and production of profibrotic factors. The main factors associated with tubulointerstitial fibrosis (TIF) are listed in Table 2.Table 2List of profibrotic factors produced by TECsFactorsEffectsReferencesTGF-βProfibrotic63Geng H. Lan R. S