miR-218 Expressed in Endothelial Progenitor Cells Contributes to the Development and Repair of the Kidney Microvasculature

Abstract

Ischemia due to hypoperfusion is one of the most common forms of acute kidney injury. We hypothesized that kidney hypoxia initiates the up-regulation of miR-218 expression in endothelial progenitor cells (EPCs) to guide endocapillary repair. Murine renal artery–derived EPCs (CD34+/CD105−) showed down-regulation of mmu-Mir218-5p/U6 RNA ratio after ischemic injury, while in human renal arteries, MIR218-5p expression was up-regulated after ischemic injury. MIR218 expression was clarified in cell culture experiments in which increases in both SLIT3 and MIR218-2-5p expressions were observed after 5 minutes of hypoxia. ROBO1 transcript, a downstream target of MIR218-2-5p, showed inverse expression to MIR218-2-5p. EPCs transfected with a MIR218-5p inhibitor in three-dimensional normoxic culture showed premature capillary formation. Organized progenitor cell movement was reconstituted when cells were co-transfected with Dicer siRNA and low-dose Mir218-5p mimic. A Mir218-2 knockout was generated to assess the significance of miR-218-2 in a mammalian model. Mir218-2-5p expression was decreased in Mir218-2−/− embryos at E16.5. Mir218-2−/− decreased CD34+ angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2+/− decreased peritubular capillary density at postnatal day 14 and increased serum creatinine after ischemia in adult mice. Systemic injection of miR-218-5p decreased serum creatinine after injury. These experiments demonstrate that miR-218 expression can be triggered by hypoxia and modulates EPC migration in the kidney. Ischemia due to hypoperfusion is one of the most common forms of acute kidney injury. We hypothesized that kidney hypoxia initiates the up-regulation of miR-218 expression in endothelial progenitor cells (EPCs) to guide endocapillary repair. Murine renal artery–derived EPCs (CD34+/CD105−) showed down-regulation of mmu-Mir218-5p/U6 RNA ratio after ischemic injury, while in human renal arteries, MIR218-5p expression was up-regulated after ischemic injury. MIR218 expression was clarified in cell culture experiments in which increases in both SLIT3 and MIR218-2-5p expressions were observed after 5 minutes of hypoxia. ROBO1 transcript, a downstream target of MIR218-2-5p, showed inverse expression to MIR218-2-5p. EPCs transfected with a MIR218-5p inhibitor in three-dimensional normoxic culture showed premature capillary formation. Organized progenitor cell movement was reconstituted when cells were co-transfected with Dicer siRNA and low-dose Mir218-5p mimic. A Mir218-2 knockout was generated to assess the significance of miR-218-2 in a mammalian model. Mir218-2-5p expression was decreased in Mir218-2−/− embryos at E16.5. Mir218-2−/− decreased CD34+ angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2+/− decreased peritubular capillary density at postnatal day 14 and increased serum creatinine after ischemia in adult mice. Systemic injection of miR-218-5p decreased serum creatinine after injury. These experiments demonstrate that miR-218 expression can be triggered by hypoxia and modulates EPC migration in the kidney. Ischemia is a leading cause of kidney injury among patients receiving health care in the United States.1Chertow G.M. Burdick E. Honour M. Bonventre J.V. Bates D.W. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.J Am Soc Nephrol. 2005; 16: 3365-3370Crossref PubMed Scopus (2502) Google Scholar, 2Best P.J. Lennon R. Ting H.H. Bell M.R. Rihal C.S. Holmes D.R. Berger P.B. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions.J Am Coll Cardiol. 2002; 39: 1113-1119Crossref PubMed Scopus (645) Google Scholar, 3Siedlecki A. Irish W. Brennan D.C. Delayed graft function in the kidney transplant.Am J Transplant. 2011; 11: 2279-2296Crossref PubMed Scopus (505) Google Scholar Endothelial cells in the renal vascular system undergo substantial damage and necrosis after an ischemic episode and do not recover as efficiently as do tubular epithelial cells (TECs).3Siedlecki A. Irish W. Brennan D.C. Delayed graft function in the kidney transplant.Am J Transplant. 2011; 11: 2279-2296Crossref PubMed Scopus (505) Google Scholar, 4Kramann R. Tanaka M. Humphreys B.D. Fluorescence microangiography for quantitative assessment of peritubular capillary changes after AKI in mice.J Am Soc Nephrol. 2014; 25: 1924-1931Crossref PubMed Scopus (86) Google Scholar, 5Venkatachalam M.A. Weinberg J.M. Kriz W. Bidani A.K. Failed tubule recovery, AKI-CKD transition, and kidney disease progression.J Am Soc Nephrol. 2015; 26: 1765-1776Crossref PubMed Scopus (414) Google Scholar Endothelial migration has long been proposed as a compensatory mechanism in the setting of reduced nephron mass but has not been investigated in the setting of ischemic kidney injury.6Sinclair R.A. Origin of endothelium in human renal allografts.Br Med J. 1972; 4: 15-16Crossref PubMed Scopus (58) Google Scholar miR-218 is recognized to play a functional role in human endothelial cells, with inhibition conferring a migratory phenotype.7Small E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google Scholar,8Pang P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar the of miR-218 has not been miR-218 is a in the of the and and These in the on 5 and and in the human on and a of is to miR-218 and both miR-218-5p in and and miR-218 has an on function by with as and cell E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google W. S. Cao C. M. regulates vascular endothelial cell the and J Google Scholar that is after of to that is the P. P. Wang J. of and injury of Res. PubMed Scopus Google Scholar The expression in endothelial progenitor cells (EPCs) and renal hypoxia has not been cells the renal been as an EPC and renal artery–derived EPCs that P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar that miR-218 to the of both the and human kidney. miR-218-5p is in EPCs both in embryos and of miR-218-5p is to hypoxia when capillary renal was that ischemic injury for minutes to that a as P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google W. a renal function in 2011; PubMed Scopus Google Scholar after was renal was was in to at the of the renal renal was the of the renal to renal was with cells were for expression in the of was with the the was generated with The was for target in a were in were were as for for PubMed Google Scholar were in the for a were for when was among and the was were for the to for A. 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A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google P. M. N. E. M. Hoffman J. Chauhan N. Mistri M. Bonventre J.V. and renal injury of 2015; PubMed Scopus Google Scholar patients a at the and which for the common system were for with a in kidney function serum creatinine the function of the kidney. 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Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar experiments were after the were to on a with and in vascular endothelial were to and in a hypoxia and with and for minutes to with the The was and in a culture was to and was after hypoxia and of cells were by of cells were The three-dimensional culture was in as P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar was R. S. C. A. Endothelial progenitor cells renal function in PubMed Scopus Google Scholar of siRNA for was with to the A of was and was endothelial cells were and to in endothelial to hypoxia experiments the as were by a kidney with for minutes at and in with serum and was and as P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google J. A. C. of and PubMed Scopus Google Scholar were for and The was the and to be in of with was on to a were with serum in with in The was with with were with a system and the was by of the were by as the the of of target to as was for the of and J. A. 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Bonventre J.V. and renal injury of 2015; PubMed Scopus Google Scholar creatinine was mass at the of miR-218-5p of was in and by to that were to adult were The injection was and were at E16.5 by in were to at which serum creatinine was of in adult was after was for for the and tubular and were for the significance was with the was for outcomes patients in cells and cells were to the to were with of at the of and M. H. N. T. M. J. H. A. C. S. function after and of in J 2014; PubMed Scopus Google Scholar The significance of the was on the in were for significance of in among with the was for for significance the of a We ischemic injury in to assess for expression in after ischemic injury were renal as P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar A and and for were to for were and were up-regulated in undergoing ischemia to expression the among and was of due to the function of miR-218 in the E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google Scholar The generated by and not the and were as not renal patients for were to miR-218 in with ischemic injury in ischemia was MIR218 expression was an for MIR218-5p and in of the to P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar cells in the of the renal were of the and cell MIR218 with a in renal function of a expression of MIR218-5p patients with a ratio of cells at the of MIR218 to an increased of kidney function that after to in MIR218 with a for kidney function in MIR218 that was the of the A mass of a of and a ischemia of minutes in that showed an in MIR218 patients an increased ischemia at of ischemia mass kidney kidney kidney kidney in a were to the and of MIR218 mass and ischemia to a in kidney The of ischemia and MIR218 expression were MIR218 ischemia with an the of an the of that miR-218-5p expression in increases after while the in the a in expression after ischemic The in the and human as to the expression of miR-218 in the renal human EPCs renal were in a to the of miR-218 and the miR-218-5p expression in the human in a of the of the miR-218-2 is to cause renal in J. Wang H. M. P. H. kidney and with in PubMed Scopus Google Scholar to the expression EPCs were to hypoxia for and minutes to assess the acute of hypoxia on miR-218 and the SLIT3 in cells of endothelial in to of S. J. expression of of and PubMed Scopus Google S. J. expression of of and PubMed Scopus Google Scholar SLIT3 was increased after 5 minutes of hypoxia SLIT3 was increased after minutes and after the up-regulation of SLIT3 after 5 minutes of hypoxia of the SLIT3 that miR-218-2 was in up-regulated and to in EPCs with SLIT3 and miR-218 expression as in normoxic E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google Scholar increased after 5 minutes of hypoxia and to after minutes of hypoxia and expression were increased the but was after 5 minutes and after minutes was increased to not the for in in the were after minutes of hypoxia. 5 minutes of the of the was increased while SLIT3 was increased transcript, for a to be functional in mammalian kidney cell J. Dicer regulates the of and ureteric in the mammalian 2011; PubMed Scopus Google Scholar, J. S. B.D. T. of and Am Soc Nephrol. PubMed Scopus Google Scholar, S. C. J. M. L.B. W. P. of and Am Soc Nephrol. PubMed Scopus Google Scholar and by C. E. T. S. S. T. A. R. A. of Dicer in which is for of and Res. PubMed Scopus Google Scholar was increased after 5 and minutes of hypoxia with a in after minutes the ratio of was increased after minutes of hypoxia of miR-218-2 with the of of and in the were to an in a of injury and of the expression in the to EPC was in decreased SLIT3 and in human endothelial cells at the miR-218-2 was up-regulated after hypoxia to and was after minutes of hypoxia. EPCs were to minutes of hypoxia by to a in which endothelial cell migration most in the clinical to an in expression observed 5 and minutes of hypoxia in the experiments in the a minutes hypoxia was ROBO1 is a target of miR-218 which migration after of endothelial progenitor and endothelial cells and was after E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google Scholar,8Pang P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar in with a normoxic ROBO1 and ROBO1 expression were decreased after minutes and increased after minutes A and ROBO1 and ROBO1 a to expression in EPC after and minutes of and were increased A reduced with cells was in a in minutes after hypoxia A in ROBO1 and ROBO1 with an in after EPC transfected with miR-218-5p not to to The in was to EPC to hypoxia by These a decreased can be with miR-218-5p of the The of MIR218-5p up-regulation in human EPCs was with cell human as a of to the cell in the J. S. M. of to the of renal tubular cells in PubMed Scopus Google Scholar We a in migration when EPCs were with A and EPCs were observed to premature capillary which was the when a of with in E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google Scholar,8Pang P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar miR-218-5p inhibition was with EPCs were in that miR-218-2 is to miR-218-5p and cells were transfected with and length was decreased in and cells EPCs a to in three-dimensional culture by in with capillary transfected with siRNA in cell co-transfected with miR-218-5p and siRNA showed cell length to and in experiments showed that EPCs kidney a of ROBO1 transcript, after hypoxia while miR-218-5p EPC SLIT3 and SLIT3 expression were up-regulated with miR-218-2 in EPCs after hypoxia. with the of a by E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google A. S. A. of mammalian and Res. PubMed Scopus Google Scholar We a to the that miR-218 expression in mammalian kidney a role in the setting of hypoxia. the clinical due to miR-218 expression in miR-218-5p in a of in human renal vascular The a that in the of 14 of the on of Mir218-2−/− cells but were nonviable. was to Mir218-5p and in the and in E16.5 The of Mir218-2 was by a in cells and an of cells by was by quantitative of Mir218-5p and in Mir218-2−/− embryos and E16.5 the ureteric bud a decreased of CD34+ angioblasts to Mir218-2+/− that was a decreased of CD34+ cells at postnatal day and decreased capillary density on postnatal day 14 Mir218-2+/− was to the significance of the on vascular miR-218 is to a functional E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google Scholar in capillary density was and serum creatinine was at in adult was increased at after the to that in serum creatinine in Mir218-2+/− undergoing were that in undergoing creatinine in Mir218-2+/− after The of miR-218 function in the kidney was after injection of miR-218-5p Mir218-2+/− by Mir218-2+/− E16.5 the ureteric bud in Mir218-2−/− embryos showed CD34+ cell density that was increased to that in Mir218-2−/− embryos serum creatinine of Mir218-2+/− undergoing injection was decreased to that in with a Mir218-2+/− Mir218-2+/− undergoing and with after injury showed serum creatinine after to that in that the injury of Mir218-2+/− at of kidney with CD34+ on day in Mir218-2+/− of peritubular capillary with and in Mir218-2+/− serum creatinine in Mir218-2+/− 14 of Mir218-2+/− after kidney injury and of adult that injury Mir218-2+/− of serum creatinine after in Mir218-2+/− at and of knockout with and in Mir218-2−/− Mir218-2−/− mimic. serum creatinine in adult Mir218-2+/− miR-218-5p in creatinine in Mir218-2+/− after and injection of miR-218-5p The of ischemic kidney injury in the that expression is in the and of mammalian renal of the the in MIR218 in Endothelial that that the expression of is to hypoxia in human the kidney. We for by that to injury in the kidney and that miR-218 to hypoxia in both and human and been with the of H. S. W. M. The role of in Res. 2014; PubMed Scopus Google M. M. R. M. of in a role for PubMed Scopus Google Scholar and kidney disease in P.J. J. N. E.M. J. as of human 2011; PubMed Scopus Google Scholar but to the role of miR-218 in of kidney miR-218 expression in kidney and hypoxia is to be for capillary function with to endothelial cells to of in was by the role of in the vascular system and J. Dicer regulates the of and ureteric in the mammalian 2011; PubMed Scopus Google M. expression of in disease Res. PubMed Scopus Google and in Res. PubMed Scopus Google Scholar The role of miR-218-5p in the of was in the decreased of angioblasts in the ureteric bud at E16.5 in with a of Mir218-2 miR-218 expression in the after is to be with hypoxia due to is is to miR-218-2 M. H. T. by for J PubMed Scopus Google Scholar that miR-218-5p and in the kidney and that the of miR-218-2 expression was to kidney due to decreased capillary in that in human and the of miR-218 expression and function in the setting of hypoxia. patterning was in experiments in which EPCs hypoxia in experiments the ischemic injury of the in experiments by endothelial cells to and of but long of hypoxia do not clinical which in M. H. T. by for J PubMed Scopus Google Scholar, T. E. R. P. M. S. M. C. A.K. M. cell and of 2014; PubMed Scopus Google Scholar, C. P. J. M. N. A. of on renal function after J PubMed Scopus Google Scholar, H. B.D. of on renal function after for clinical renal cell a PubMed Scopus Google Scholar, H. H. R. renal function after with PubMed Scopus Google Scholar minutes of ischemia in patients undergoing observed a that an in miR-218 expression and a in ischemia in experiments in which miR-218 expression to after minutes of hypoxia miR-218 has been to the downstream of in a T. of by on in endothelial cells Google Scholar We to by the acute of miR-218 to EPC injury to the of showed that miR-218-5p and expression in EPCs both an in and was increased after minutes of hypoxia and with increased Dicer SLIT3 expression has been after of S. J. expression of of and PubMed Scopus Google Scholar while has been to after and SLIT3 expression in endothelial cells after of hypoxia was not P.J. Wang M. A.K. H. M. of Dicer in the to PubMed Scopus Google C. E. T. S. S. T. A. R. A. of Dicer in which is for of and Res. PubMed Scopus Google Scholar an up-regulation in that miR-218-2 was in the human EPC to acute hypoxia. clinical was by expression of a A in MIR218 expression after of ischemic injury by the miR-218-5p expression in is to play an role in cell that to cell E.M. Sutherland L.B. Rajagopalan K.N. Wang S. Olson E.N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.Circ Res. 2010; 107: 1336-1344Crossref PubMed Scopus (126) Google Scholar,8Pang P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar investigated the function of miR-218-5p to in to the of miR-218-2 expression in human capillary when by hypoxia. and in 14 of is to cause renal in but not been investigated in human J. Wang H. M. P. H. kidney and with in PubMed Scopus Google Scholar showed MIR218-2-5p, and were up-regulated after to hypoxia and with a in ROBO1 expression of the inhibition of miR-218-5p in human EPCs was with endothelial to in miR-218-5p expression was reconstituted at cell length increased in three-dimensional that the endothelial migratory a expression of miR-218-2 to cell The migration of was by miR-218 inhibition but not capillary P. Abbott M. Chang S.L. Abdi M. Chauhan N. Mistri M. Ghofrani J. Fucci Q.A. Walker C. Leonardi C. Grady S. Halim A. Hoffman R. Lu T. Cao H. Tullius S. S. A. vascular progenitor cells renal and in the of renal capillary PubMed Scopus Google Scholar The of miR-218-5p with Dicer siRNA a of miR-218 by in the setting of capillary formation. inhibition in was not as as hypoxia. The setting and that in EPCs the kidney injection of miR-218-5p in Mir218-2+/− and the of miR-218-2 in the and of kidney The of injection in was by the in serum creatinine in Mir218-2+/− that in of in Mir218-2+/− after by in serum creatinine after injury the of miR-218 in kidney were to that the not with A. Tullius J. of a of renal ischemia A. 2010; 107: PubMed Scopus Google Scholar in the setting of ischemic kidney injury. These be by the of cell in kidney after ischemic kidney injury and the kidney after hypoxia. miR-218 is to be in knockout experiments for the function of in in which function be due to a of cell that and miR-218 to We miR-218-2 as an of vascular and in CD34+ These the to that can renal function after the of in the setting of ischemic injury.

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