Cellular communication network 2 (connective tissue growth factor) aggravates acute DNA damage and subsequent DNA damage response-senescence-fibrosis following kidney ischemia reperfusion injury

Abstract

Chronic allograft dysfunction with progressive fibrosis of unknown cause remains a major issue after kidney transplantation, characterized by ischemia-reperfusion injury (IRI). One hypothesis to account for this is that spontaneous progressive tubulointerstitial fibrosis following IRI is driven by cellular senescence evolving from a prolonged, unresolved DNA damage response (DDR). Since cellular communication network factor 2 ((CCN2), formerly called connective tissue growth factor), an established mediator of kidney fibrosis, is also involved in senescence-associated pathways, we investigated the relation between CCN2 and cellular senescence following kidney transplantation. Tubular CCN2 overexpression was found to be associated with DDR, loss of kidney function and tubulointerstitial fibrosis in both the early and the late phase in human kidney allograft biopsies. Consistently, CCN2 deficient mice developed reduced senescence and tubulointerstitial fibrosis in the late phase; six weeks after experimental IRI. Moreover, tubular DDR markers and plasma urea were less elevated in CCN2 knockout than in wild-type mice. Finally, CCN2 administration or overexpression in epithelial cells induced upregulation of tubular senescence–associated genes including p21, while silencing of CCN2 alleviated DDR induced by anoxia-reoxygenation injury in cultured proximal tubule epithelial cells. Thus, our observations indicate that inhibition of CCN2 can mitigate IRI-induced acute kidney injury, DNA damage, and the subsequent DDR-senescence-fibrosis sequence. Hence, targeting CCN2 might help to protect the kidney from transplantation-associated post-IRI chronic kidney dysfunction. Chronic allograft dysfunction with progressive fibrosis of unknown cause remains a major issue after kidney transplantation, characterized by ischemia-reperfusion injury (IRI). One hypothesis to account for this is that spontaneous progressive tubulointerstitial fibrosis following IRI is driven by cellular senescence evolving from a prolonged, unresolved DNA damage response (DDR). Since cellular communication network factor 2 ((CCN2), formerly called connective tissue growth factor), an established mediator of kidney fibrosis, is also involved in senescence-associated pathways, we investigated the relation between CCN2 and cellular senescence following kidney transplantation. Tubular CCN2 overexpression was found to be associated with DDR, loss of kidney function and tubulointerstitial fibrosis in both the early and the late phase in human kidney allograft biopsies. Consistently, CCN2 deficient mice developed reduced senescence and tubulointerstitial fibrosis in the late phase; six weeks after experimental IRI. Moreover, tubular DDR markers and plasma urea were less elevated in CCN2 knockout than in wild-type mice. Finally, CCN2 administration or overexpression in epithelial cells induced upregulation of tubular senescence–associated genes including p21, while silencing of CCN2 alleviated DDR induced by anoxia-reoxygenation injury in cultured proximal tubule epithelial cells. Thus, our observations indicate that inhibition of CCN2 can mitigate IRI-induced acute kidney injury, DNA damage, and the subsequent DDR-senescence-fibrosis sequence. Hence, targeting CCN2 might help to protect the kidney from transplantation-associated post-IRI chronic kidney dysfunction. Translational StatementOur data suggest that anti–cellular communication network factor 2 (CCN2) therapy may help to prevent chronic allograft dysfunction by limiting ischemia-reperfusion injury (IRI)–induced acute DNA damage, senescent cell accumulation, and subsequent tubulointerstitial fibrosis. Anti-CCN2 therapy could therefore improve graft function and survival outcomes in patients. Several pharmacologic inhibitors of CCN2 have proven safe and tolerable in phase 1 and/or 2 clinical trials for several indications, including senescence- and fibrosis-associated diseases. The next steps toward clinical application of anti-CCN2 therapy in patients who underwent kidney transplantation include experimental IRI studies using pharmacologic inhibitors of CCN2 and addressing the right timing of therapy. Chronic allograft dysfunction (CAD) due to tubulointerstitial fibrosis is the leading cause of kidney allograft loss and may develop without identifiable cause, despite adequate immunosuppression. Ischemia-reperfusion injury (IRI), in which ischemia is followed by reoxygenation injury, is the main cause of acute kidney injury associated with transplantation surgery and considered a major cause of CAD. CAD is defined by progressive tubulointerstitial fibrosis, functional decline, and eventual loss of the kidney graft.1Situmorang G.R. Sheerin N.S. Ischaemia reperfusion injury mechanisms of progression to chronic graft dysfunction.Pediatr Nephrol. 2019; 34: 951-963Crossref PubMed Scopus (18) Google Scholar,2Li C. Yang C.W. The pathogenesis and treatment of chronic allograft nephropathy.Nat Rev Nephrol. 2009; 5: 513-519Crossref PubMed Scopus (102) Google Scholar Short-term allograft survival has improved substantially over the past decades, but long-term outcomes remain poor.3Wekerle T. Segev D. Lechler R. Oberbauer R. Strategies for long-term preservation of kidney graft function.Lancet. 2017; 389: 2152-2162Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar,4Lamb K.E. Lodhi S. Meier-Kriesche H.-U. Long-term renal allograft survival in the United States: a critical reappraisal.Am J Transplant. 2011; 11: 450-462Crossref PubMed Scopus (671) Google Scholar Given the high demand for suitable donor kidneys and their limited availability, prolonging survival of allografts is of utmost importance. Cell cycle arrest (CCA) is a physiological process and essential for the repair of DNA damage immediately after injury.5Branzei D. Foiani M. Regulation of DNA repair throughout the cell cycle.Nat Rev Mol Cell Biol. 2008; 9: 297-308Crossref PubMed Scopus (893) Google Scholar Unsuccessful DNA repair either results in apoptosis or alternatively, in cellular senescence with persistence of a DNA damage response (DDR). Cellular senescence has been defined as a state of persistent, irreversible CCA that may lead to detrimental adverse tissue remodeling via dedifferentiation and by the associated phenomenon dubbed the senescence-associated secretory phenotype (SASP) characterized by the secretion of proinflammatory and profibrotic stimuli.6Gorgoulis V. Adams P.D. Alimonti A. et al.Cellular senescence: defining a path forward.Cell. 2019; 179: 813-827Abstract Full Text Full Text PDF PubMed Scopus (770) Google Scholar, 7Gire V. Dulic V. 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Brandt R.M.C. Putavet D.A. et al.Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging.Cell. 2017; 169 (e16): 132-147Abstract Full Text Full Text PDF PubMed Scopus (730) Google Scholar In unilateral IRI, treatment with the “senolytic” agents dasatinib and quercetin reduced tubulointerstitial fibrosis.16Li C. Shen Y. Huang L. et al.Senolytic therapy ameliorates renal fibrosis postacute kidney injury by alleviating renal senescence.FASEB J. 2021; 35: e21229PubMed Google Scholar Cellular communication network factor 2 (CCN2), previously known as connective tissue growth factor, is a matricellular protein involved in IRI and fibrosis. It contributes to tubulointerstitial fibrosis in CAD and has successfully been targeted to limit fibrosis.17Falke L.L. Goldschmeding R. Nguyen T.Q. A perspective on anti-CCN2 therapy for chronic kidney disease.Nephrol Dial Transplant. 2014; 29: i30-i37Crossref PubMed Scopus (21) Google Scholar CCN2 is involved in various processes, including cell proliferation, differentiation, adhesion, and angiogenesis, and promotes inflammation and fibrosis.17Falke L.L. Goldschmeding R. Nguyen T.Q. A perspective on anti-CCN2 therapy for chronic kidney disease.Nephrol Dial Transplant. 2014; 29: i30-i37Crossref PubMed Scopus (21) Google Scholar, 18Ramazani Y. Knops N. Elmonem M.A. et al.Connective tissue growth factor (CTGF) from basics to clinics.Matrix Biol. 2018; 68-69: 44-66Crossref PubMed Scopus (152) Google Scholar, 19Sánchez-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 (97) Google Scholar CCN2 is also implicated in cellular senescence. It is not only a prominent SASP factor but can also function by itself as a cellular survival factor and as an inducer of cellular senescence in vitro.20Yang L. Besschetnova T.Y. Brooks C.R. et al.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med. 2010; 16: 143-535Crossref Scopus (892) Google Scholar, 21Wahab N. Cox D. Witherden A. Mason R.M. Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1).Biochem J. 2007; 406: 131-138Crossref PubMed Scopus (42) Google Scholar, 22Jun J.I. Lau L.F. CCN2 induces cellular senescence in fibroblasts.J Cell Commun Signal. 2017; 11: 15-23Crossref PubMed Scopus (30) Google Scholar Observing colocalization of CCN2 with DDR and senescence markers in an early and late biopsy of the same human kidney allograft led us to hypothesize that CCN2 could contribute to senescent cell accumulation and tubulointerstitial fibrosis during CAD development after IRI. To elucidate this hypothesis, we investigated the relation between CCN2 and cellular senescence in the early and late phase of human kidney allograft biopsies, in a bilateral IRI model in CCN2 knockout (KO) mice, in CCN2-treated mice and cultured cells, and finally, in an anoxia-reoxygenation (AR) model in CCN2-silenced cultured cells. Tissue sections were derived from routine clinical kidney allograft biopsies at the University Medical Center Utrecht. 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DDR was in and cells. of with CCN2 the of and protein and an by reduced and Moreover, the of and SASP and 2 and were by In in cells, CCN2 overexpression in of p21, and and and an of cells in the G2/M phase The of CCN2 on DDR in tubular cells was by silencing CCN2 in to injury, as an in model for T. et due to ischemia or reperfusion in renal tubular epithelial cells from or the 2018; Scholar upregulation of and was alleviated CCN2 was with the of cells that were cultured and of CCA in CCN2-silenced cells and Finally, the of was in CCN2-silenced cells and J. N. Yang et of the senescence marker in predicts reduced 2015; Scopus Google Scholar observations in human kidney allograft biopsies an of with tubular CCN2 DDR, and cellular senescence, a by transplantation surgery–induced IRI. is by our experimental data that CCN2 kidney function and tubulointerstitial fibrosis and tubular senescence weeks after IRI. this is by preserved kidney function and reduced tubular DDR, despite acute tubular damage days after IRI. The of CCN2 on proximal tubular DDR is by in data that CCN2 silencing in also DDR and CCN2 administration induces in and in CCN2 has previously been to contribute to fibrosis development in T. H. 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Lau L.F. CCN2 induces cellular senescence in fibroblasts.J Cell Commun Signal. 2017; 11: 15-23Crossref PubMed Scopus (30) Google Scholar could be by a role of cellular senescence in including and on V. M. et of activated cells 2008; Full Text Full Text PDF PubMed Scopus Google M. N. et essential role for senescent cells in secretion of Cell. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar of CCN2 inhibition have not been in the of renal The main mechanisms of CCN2 contributes to IRI-induced senescence might DDR and the IRI induces DNA damage in tubular epithelial cells and subsequent DDR to of the A. et cause chronic kidney to DNA damage PubMed Scopus Google Scholar DNA damage to DDR, evolving in cellular senescence of the tubular days of injury that over H. Y. et al.Epithelial mediates tubular cell senescence after kidney 2019; PubMed Scopus Google Scholar senescence in cultured cells is the accumulation of cell cycle and J.I. Lau L.F. CCN2 induces cellular senescence in fibroblasts.J Cell Commun Signal. 2017; 11: 15-23Crossref PubMed Scopus (30) Google N. T. Mason R.M. Connective tissue growth factor and of the mesangial cell role in cellular Am Soc Nephrol. PubMed Scopus (105) Google S. et al.Connective tissue growth factor promotes epithelial cell senescence and is associated with 2017; 14: PubMed Scopus Google Scholar with a role for CCN2 in the development of a senescence phenotype, we that DDR was in CCN2 mice in the early phase of IRI and in CCN2 to injury, and that CCN2 induced that CCN2 the development of a senescence phenotype by DDR and subsequent CCA in the early phase renal The SASP promotes fibrosis and the and contributes to senescence Y. C. et of the senescence-associated secretory phenotype by promotes senescence and 2011; PubMed Scopus Google Scholar, V. K. et and a in 2019; PubMed Scopus Google Scholar, M. T. et improve function and in Med. 2018; PubMed Scopus Google Scholar The development of the SASP on the of several including factor Y. C. et of the senescence-associated secretory phenotype by promotes senescence and 2011; PubMed Scopus Google Scholar CCN2 factor in induces of SASP including and in cultured and is itself also a of SASP in senescent renal tubular epithelial 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 (97) Google L. Besschetnova T.Y. Brooks C.R. et al.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med. 2010; 16: 143-535Crossref Scopus (892) Google J.I. Lau L.F. CCN2 induces cellular senescence in fibroblasts.J Cell Commun Signal. 2017; 11: 15-23Crossref PubMed Scopus (30) Google Y. C. et of the senescence-associated secretory phenotype by promotes senescence and 2011; PubMed Scopus Google L. M. et by promotes G2/M arrest and renal fibrosis in and in Mol Cell Biol. 2019; 11: PubMed Scopus Google Scholar Moreover, tubular of the SASP factor promotes G2/M arrest, and tubular repair CCN2 J. et during kidney injury promotes epithelial dysfunction via of and J. 2021; 35: PubMed Scopus Google Scholar In the late phase IRI, we that CCN2 kidneys reduced upregulation of SASP that reduced and senescence might at in the of reduced fibrosis with reduced accumulation of senescent cells. In our data to the role of CCN2 in kidney fibrosis that a role also early in the development of tubular damage and subsequent tubulointerstitial fibrosis after IRI, in in the DNA sequence. that therapy might graft function and survival outcomes of patients who underwent kidney transplantation and of pharmacologic in the early and of IRI. from University Medical Center during the of the from the during the of the from the Medical during the of the and from the during the of the other is by and was with a is by and was with a for the of CCN2 knockout mice by of and University of with Tubular of cellular communication network factor 2 (CCN2) was not associated with DNA damage response in late kidney allograft biopsies with kidney function and DDR in early kidney allograft biopsies. Tubular of cellular communication network factor 2 (CCN2) with DNA damage response in late and early kidney allograft biopsies. of cellular communication network factor 2 (CCN2) reduced CCN2 protein weeks after ischemia-reperfusion injury (IRI). of cellular communication network factor 2 (CCN2) results in reduced plasma days after ischemia-reperfusion injury and in plasma weeks after IRI. of cellular communication network factor 2 (CCN2) results in of and apoptosis days after ischemia-reperfusion injury (IRI). Cellular communication network factor 2 (CCN2) knockout with CCN2 plasma acute tubular injury, and in CCN2 knockout (KO) mice days after ischemia-reperfusion injury (IRI). for

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