Abstract
Background. Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis, and arteriolar hypertrophy. While the molecular mechanisms of CsA toxicity are not well characterized, previous studies have demonstrated that altered arachidonic acid (AA) metabolism plays a role its pathogenesis. Using a rat renal transplant model, the purpose of this study was to examine the effects of CsA on the 5-lipoxygenase (5-LO) pathway of AA metabolism. Methods. The PVG (RT1c) strain of rats underwent kidney transplantation, and recipients of nonrejecting kidney transplants were treated with either 50 mg/kg/day CsA or vehicle (N = 24). To determine the physiologic significance of increased leukotriene (LT) production, the peptidoleukotriene receptor antagonist SKF 106203 was administered to CsA- treated animals for six days. Results. CsA caused a substantial reduction in glomerular filtration rate (GFR) in the transplanted rats compared with the vehicle-treated controls (1.5 ± 0.6 vs. 4.1 ± 0.8 mL/min/kg, P < 0.05). The reduction in renal function was associated with enhanced urinary excretion of the peptidoleukotriene metabolites LTE4 (1431 ± 207 vs. 953 ± 125 pg/24 h, P < 0.05) and N-acetyl-LTE4 (4411 ± 848 vs. 463 ± 70 pg/24 h, P < 0.001). LT receptor blockade had a significant protective effect on renal transplant function in CsA-treated animals (GFR, 4.8 ± 1.1 vs. 1.7 ± 0.9 mL/min/kg, P < 0.05), such that CsA-treated animals that received SKF106203 maintained GFR at levels similar to controls that never received CsA (4.1 ± 0.8 mL/min/kg). Peptidoleukotriene receptor blockade also prevented the histomorphological abnormalities caused by CsA, including tubular vacuolization. Conclusions. These studies identify a critical role for LTs in the pathophysiology of CsA nephrotoxicity and suggest that LT antagonists may be useful in preventing CsA-associated kidney toxicity.
| Original language | English |
|---|---|
| Pages (from-to) | 2586-2593 |
| Number of pages | 8 |
| Journal | Kidney International |
| Volume | 57 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 20 2000 |
| Externally published | Yes |
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Keywords
- 5-lipoxygenase pathway
- Arachidonic acid
- Kidney toxicity
- Peptidoleukotriene receptor blockade
- Tubular vacuolization
ASJC Scopus subject areas
- Nephrology
Cite this
A role for leukotrienes in cyclosporine nephrotoxicity. / Butterly, David W.; Spurney, Robert F.; Ruiz, Phillip; Griffiths, Robert; Albrightson, Christine; Coffman, Thomas M.
In: Kidney International, Vol. 57, No. 6, 20.06.2000, p. 2586-2593.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A role for leukotrienes in cyclosporine nephrotoxicity
AU - Butterly, David W.
AU - Spurney, Robert F.
AU - Ruiz, Phillip
AU - Griffiths, Robert
AU - Albrightson, Christine
AU - Coffman, Thomas M.
PY - 2000/6/20
Y1 - 2000/6/20
N2 - Background. Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis, and arteriolar hypertrophy. While the molecular mechanisms of CsA toxicity are not well characterized, previous studies have demonstrated that altered arachidonic acid (AA) metabolism plays a role its pathogenesis. Using a rat renal transplant model, the purpose of this study was to examine the effects of CsA on the 5-lipoxygenase (5-LO) pathway of AA metabolism. Methods. The PVG (RT1c) strain of rats underwent kidney transplantation, and recipients of nonrejecting kidney transplants were treated with either 50 mg/kg/day CsA or vehicle (N = 24). To determine the physiologic significance of increased leukotriene (LT) production, the peptidoleukotriene receptor antagonist SKF 106203 was administered to CsA- treated animals for six days. Results. CsA caused a substantial reduction in glomerular filtration rate (GFR) in the transplanted rats compared with the vehicle-treated controls (1.5 ± 0.6 vs. 4.1 ± 0.8 mL/min/kg, P < 0.05). The reduction in renal function was associated with enhanced urinary excretion of the peptidoleukotriene metabolites LTE4 (1431 ± 207 vs. 953 ± 125 pg/24 h, P < 0.05) and N-acetyl-LTE4 (4411 ± 848 vs. 463 ± 70 pg/24 h, P < 0.001). LT receptor blockade had a significant protective effect on renal transplant function in CsA-treated animals (GFR, 4.8 ± 1.1 vs. 1.7 ± 0.9 mL/min/kg, P < 0.05), such that CsA-treated animals that received SKF106203 maintained GFR at levels similar to controls that never received CsA (4.1 ± 0.8 mL/min/kg). Peptidoleukotriene receptor blockade also prevented the histomorphological abnormalities caused by CsA, including tubular vacuolization. Conclusions. These studies identify a critical role for LTs in the pathophysiology of CsA nephrotoxicity and suggest that LT antagonists may be useful in preventing CsA-associated kidney toxicity.
AB - Background. Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis, and arteriolar hypertrophy. While the molecular mechanisms of CsA toxicity are not well characterized, previous studies have demonstrated that altered arachidonic acid (AA) metabolism plays a role its pathogenesis. Using a rat renal transplant model, the purpose of this study was to examine the effects of CsA on the 5-lipoxygenase (5-LO) pathway of AA metabolism. Methods. The PVG (RT1c) strain of rats underwent kidney transplantation, and recipients of nonrejecting kidney transplants were treated with either 50 mg/kg/day CsA or vehicle (N = 24). To determine the physiologic significance of increased leukotriene (LT) production, the peptidoleukotriene receptor antagonist SKF 106203 was administered to CsA- treated animals for six days. Results. CsA caused a substantial reduction in glomerular filtration rate (GFR) in the transplanted rats compared with the vehicle-treated controls (1.5 ± 0.6 vs. 4.1 ± 0.8 mL/min/kg, P < 0.05). The reduction in renal function was associated with enhanced urinary excretion of the peptidoleukotriene metabolites LTE4 (1431 ± 207 vs. 953 ± 125 pg/24 h, P < 0.05) and N-acetyl-LTE4 (4411 ± 848 vs. 463 ± 70 pg/24 h, P < 0.001). LT receptor blockade had a significant protective effect on renal transplant function in CsA-treated animals (GFR, 4.8 ± 1.1 vs. 1.7 ± 0.9 mL/min/kg, P < 0.05), such that CsA-treated animals that received SKF106203 maintained GFR at levels similar to controls that never received CsA (4.1 ± 0.8 mL/min/kg). Peptidoleukotriene receptor blockade also prevented the histomorphological abnormalities caused by CsA, including tubular vacuolization. Conclusions. These studies identify a critical role for LTs in the pathophysiology of CsA nephrotoxicity and suggest that LT antagonists may be useful in preventing CsA-associated kidney toxicity.
KW - 5-lipoxygenase pathway
KW - Arachidonic acid
KW - Kidney toxicity
KW - Peptidoleukotriene receptor blockade
KW - Tubular vacuolization
UR - http://www.scopus.com/inward/record.url?scp=0008785118&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0008785118&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.2000.00118.x
DO - 10.1046/j.1523-1755.2000.00118.x
M3 - Article
C2 - 10844628
AN - SCOPUS:0008785118
VL - 57
SP - 2586
EP - 2593
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 6
ER -