TY - JOUR
T1 - Anomalous renal effects of tin protoporphyrin in a murine model of sickle cell disease
AU - Juncos, Julio P.
AU - Grande, Joseph P.
AU - Murali, Narayana
AU - Croatt, Anthony J.
AU - Juncos, Luis A.
AU - Hebbel, Robert P.
AU - Katusic, Zvonimir S.
AU - Nath, Karl A.
N1 - Funding Information:
Supported by the National Institutes of Health (grants PPG HL-55552 to K.A.N., Z.S.K., and R.P.H.; and DK 47060 to K.A.N.).
PY - 2006/7
Y1 - 2006/7
N2 - 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 tubulo-interstitial 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 con-firmed. 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.
AB - 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 tubulo-interstitial 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 con-firmed. 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.
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U2 - 10.2353/ajpath.2006.051195
DO - 10.2353/ajpath.2006.051195
M3 - Article
C2 - 16816358
AN - SCOPUS:33745686480
SN - 0002-9440
VL - 169
SP - 21
EP - 31
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -