title: Podocytes protect glomerular endothelial cells from hypoxic injury via deSUMOylation of HIF-1α signaling.
abstract: Hypoxia can cause severe tubulointerstitial injury and peritubular capillary loss. However, hypoxia-induced injury in glomerular capillaries is far milder than tubulointerstitium, but the reason for this difference is unclear. We hypothesized that the phenomenon is due to the protective crosstalk among intrinsic glomerular cells. To mimic the microenvironment and investigate the crosstalk process temporally, we established co-culture models of glomerular endothelial cells (GEnCs) with podocytes or with mesangial cells. We found that podocytes rather than mesangial cells prevented GEnCs from injury and hypoxia-induced apoptosis and promoted migration and angiogenesis of GEnCs under hypoxic conditions. We then identified that increased activation of the hypoxia inducible factor 1α (HIF-1α) pathway as the major mechanism enabling podocytes to protect GEnCs against hypoxia. HIF-1α stabilization during hypoxia is known to be dependent on SUMO-specific protease 1 (SENP1)-mediated deSUMOylate modifications. Therefore, we further targeted deSUMOylation, regulated by SENP1, by short hairpin RNA (shRNA) knockdown of SENP1 mRNA in vitro and measured expression of HIF-1α and its downstream gene VEGF in hypoxic podocytes. Our results showed that SENP1 was essential for HIF-1α deSUMOylation in podocytes. The blockade of deSUMOylation by SENP1 shRNA successfully abolished the activation of HIF-1α signaling and consequently suppressed the protective effects of podocytes on GEnCs. In conclusion, we demonstrate for the first time that hypoxia may promote HIF-1α stabilization and activation by increasing SENP1 expression in podocytes, which induce GEnCs survival and angiogenesis to resist hypoxia. Thus, deSUMOylation of HIF-1α signaling is a potentially novel therapeutic target for treating hypoxic renal disorders.
authors.affiliation: Graduate School of Dalian Medical University, Dalian, China; Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Tuaner
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Graduate School of Dalian Medical University, Dalian, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Teng
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, Beijing, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China. Electronic address: linhongli@vip.163.com.
authors.forename: Hongli
authors.initials: H
authors.lastname: Lin
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D047468:Immunoprecipitation; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse
keywords: Glomerular endothelial cell; Hypoxia; Hypoxia inducible factor 1α; Podocyte; SUMO-specific protease 1