EPO and alpha-MSH prevent ischemia/reperfusion-induced down-regulation of AQPs and sodium transporters in rat kidney

Kidney Int. 2004 Aug;66(2):683-95. doi: 10.1111/j.1523-1755.2004.00791.x.


Background: Ischemia-induced acute renal failure (ARF) is known to be associated with significant impairment of urinary concentrating ability and down-regulation of renal aquaporins (AQPs) and sodium transporters in rats. We tested whether treatment with erythropoietin (EPO) or alpha-melanocyte-stimulating hormone (alpha-MSH) in combination with EPO reduces the renal ischemia/reperfusion (I/R) injury and prevents the down-regulation of renal AQPs and major sodium transporters.

Methods: I/R-induced ARF was established in rats by 40-minute temporary bilateral obstruction of renal arteries, and rats were kept in metabolic cages for urine measurements. After 2 or 4 days following EPO and/or alpha-MSH treatment, kidneys were removed to determine the expression levels of AQPs and sodium transporters by semiquantitative immunoblotting.

Results: Rats with ARF showed significant renal insufficiency, increased urine output, and high fractional excretion of urinary sodium. Consistent with this, immunoblotting and immunocytochemistry revealed that the kidney expression of AQPs (AQP-1, -2 and -3) and sodium transporters [Na,K-ATPase, rat type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), Na/H exchanger type 3 (NHE3), and thiazide-sensitive sodium chloride cotransporter (TSC)] in ARF rats was significantly decreased compared to sham-operated control rats. In contrast, EPO treatment at the time of ischemia of rats with ARF significantly prevented the ischemia-induced down-regulation of renal AQPs and sodium transporters and in parallel improved the urinary concentrating capability and renal sodium reabsorption. Importantly, similar effects were observed following the initiation of EPO or alpha-MSH treatment 4 hours after the onset of ischemia injury. Moreover, the combination of EPO with alpha-MSH potentiated the beneficial effects of single compound treatment.

Conclusion: EPO and/or alpha-MSH treatment significantly prevent I/R-induced injuries such as urinary-concentrating defects and down-regulation of renal AQPs and sodium transporters.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / metabolism
  • Animals
  • Antibody Specificity
  • Aquaporin 1
  • Aquaporin 2
  • Aquaporin 3
  • Aquaporins / immunology
  • Aquaporins / metabolism*
  • Down-Regulation / drug effects
  • Erythropoietin / pharmacology*
  • Immunoblotting
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / metabolism
  • Sodium / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Water / metabolism
  • alpha-MSH / pharmacology*


  • Aqp1 protein, rat
  • Aqp2 protein, rat
  • Aqp3 protein, rat
  • Aquaporin 2
  • Aquaporins
  • Slc9a3 protein, rat
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Water
  • Erythropoietin
  • Aquaporin 1
  • Aquaporin 3
  • alpha-MSH
  • Sodium
  • Sodium-Potassium-Exchanging ATPase