Early and prominent alterations in hemodynamics, signaling, and gene expression following renal ischemia in sickle cell disease

Julio P. Juncos, Joseph P. Grande, Anthony J. Croatt, Robert P. Hebbel, Gregory M. Vercellotti, Zvonimir S. Katusic, Karl A. Nath

Research output: Contribution to journalArticle

21 Scopus citations

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-α. Inducibility of anti-inflammatory, cytoprotective genes, such as heme oxygenase-1 and IL-10, was not impaired in 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.

Original languageEnglish (US)
Pages (from-to)F892-F899
JournalAmerican Journal of Physiology - Renal Physiology
Volume298
Issue number4
DOIs
StatePublished - Apr 1 2010

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Keywords

  • Acute kidney injury
  • Heme oxygenase
  • Inflammation
  • MAPK proteins
  • Nitric oxide synthase
  • Vasoocclusion

ASJC Scopus subject areas

  • Physiology
  • Urology

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