title: SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease.
abstract: The progressive decline of renal function in chronic kidney disease (CKD) is characterized by both disruption of the microvascular architecture and the accumulation of fibrotic matrix. One angiogenic pathway recently identified as playing an essential role in renal vascular development is the stromal cell-derived factor-1α (SDF-1)/CXCR4 pathway. Because similar developmental processes may be recapitulated in the disease setting, we hypothesized that the SDF-1/CXCR4 system would regulate microvascular health in CKD. Expression of CXCR4 was observed to be increased in the kidneys of subtotally nephrectomized (SNx) rats and in biopsies from patients with secondary focal segmental glomerulosclerosis (FSGS), a rodent model and human correlate both characterized by aberration of the renal microvessels. A reno-protective role for local SDF-1/CXCR4 signaling was indicated by i) CXCR4-dependent glomerular eNOS activation following acute SDF-1 administration; and ii) acceleration of renal function decline, capillary loss and fibrosis in SNx rats treated with chronic CXCR4 blockade. In contrast to the upregulation of CXCR4, SDF-1 transcript levels were decreased in SNx rat kidneys as well as in renal fibroblasts exposed to the pro-fibrotic cytokine transforming growth factor β (TGF-β), the latter effect being attenuated by histone deacetylase inhibition. Increased renal SDF-1 expression was, however, observed following the treatment of SNx rats with the ACE inhibitor, perindopril. Collectively, these observations indicate that local SDF-1/CXCR4 signaling functions to preserve microvascular integrity and prevent renal fibrosis. Augmentation of this pathway, either purposefully or serendipitously with either novel or existing therapies, may attenuate renal decline in CKD.
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Li-Hao
authors.initials: LH
authors.lastname: Chen
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: M Golam
authors.initials: MG
authors.lastname: Kabir
authors.affiliation: Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Manish M
authors.initials: MM
authors.lastname: Sood
authors.affiliation: Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Gibson
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Darren A
authors.initials: DA
authors.lastname: Yuen
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.affiliation: Department of Medicine, St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
mesh_terms: D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001596:Benzylamines; D001706:Biopsy; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D000080027:Cyclams; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D007677:Kidney Function Tests; D009392:Nephrectomy; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D012694:Serine; D052250:Nitric Oxide Synthase Type III; C088327:plerixafor; D020913:Perindopril