Anomalous renal effects of tin protoporphyrin in a murine model of sickle cell disease.
In human and murine models of sickle cell disease (SCD), heme oxygenase-1 (HO-1) is induced in the kidney, an organ commonly involved in SCD. The present study assessed the role of HO-1 by using a competitive inhibitor of HO activity, tin protoporphyrin (SnPP), in protocols affording a composite, clinically relevant analysis of the kidney in SCD under unstressed and stressed conditions. Whereas short-term administration of SnPP exerted comparable renal hemodynamic effects in wild-type and sickle mice, chronic administration of SnPP exerted divergent effects: SnPP provoked tubulointerstitial inflammation and up-regulation of injury-related genes in wild-type mice, whereas in sickle mice SnPP reduced expression of injury-related genes and vascular congestion without provoking tubulointerstitial inflammation. SnPP also protected against the heightened sensitivity to renal ischemia observed in sickle mice, preventing ischemia-induced worsening of renal injury in sickle mice above that observed in wild-type mice. Effective and comparable inhibition of HO activity by SnPP in wild-type and sickle mice was confirmed. These findings suggest that induction of HO-1, at least as assessed by this approach, may contribute to renal injury in this murine model of SCD and uncover an experimental maneuver that protects the kidney in murine SCD.
Juncos
Julio P
JP
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Grande
Joseph P
JP
Murali
Narayana
N
Croatt
Anthony J
AJ
Juncos
Luis A
LA
Hebbel
Robert P
RP
Katusic
Zvonimir S
ZS
Nath
Karl A
KA
D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006450:Hemoglobin SC Disease / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D007677:Kidney Function Tests; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D011524:Protoporphyrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1