title: Early and prominent alterations in hemodynamics, signaling, and gene expression following renal ischemia in sickle cell disease.
abstract: Acute ischemic insults to the kidney are recognized complications of human sickle cell disease (SCD). The present study analyzed in a transgenic SCD murine model the early renal response to acute ischemia. Renal hemodynamics were profoundly impaired following ischemia in sickle mice compared with wild-type mice: glomerular filtration rate, along with renal plasma flow and blood flow rates, were markedly reduced, while renal vascular resistances were increased more than threefold in sickle mice following ischemia. In addition to these changes in renal hemodynamics, there were profound disturbances in renal signaling processes: phosphorylation of members of the MAPK and Akt signaling proteins occurred in the kidney in wild-type mice after ischemia, whereas such phosphorylation did not occur in the kidney in sickle mice after ischemia. ATP content in the postischemic kidney in sickle mice was less than half that observed in wild-type mice. Examination of the expression of candidate genes uncovered changes that may predispose to increased sensitivity of the kidney in sickle mice to ischemia: increased expression of inducible nitric oxide synthase and decreased expression of endothelial nitric oxide synthase, and increased expression of TNF-alpha. Inducibility of anti-inflammatory, cytoprotective genes, such as heme oxygenase-1 and IL-10, was not impaired in sickle mice after ischemia. We conclude that the kidney in SCD is remarkably vulnerable to acute ischemic insults. We speculate that such sensitivity of the kidney to ischemia in SCD may underlie the occurrence of acute kidney injury in patients with SCD and may set the stage for the emergence of chronic kidney disease in SCD.
authors.affiliation: Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Julio P
authors.initials: JP
authors.lastname: Juncos
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006439:Hemodynamics; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000145:classification / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012805:Sickle Cell Trait / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases