Abstract
Background/Aims: The etiology of renal dysfunction in cancer patients is likely to be multifactorial. A large proportion of these patients receive opioid analgesics, but whether opioids contribute to renal dysfunction remains uncertain. In a murine cancer model, we examined the effects of chronic opioid administration on renal function and pathology, and the molecular mechanisms involved. Methods: C3H/HeJ mice implanted with 2472 tumor cells were treated with either morphine or hydromorphone in clinically relevant doses, or PBS (controls). Renal function was assessed by blood and urine chemistry as well as by measuring mean arterial pressure (MAP) and kidney perfusion. Pathological changes in the kidneys were examined by routine histology. Molecular changes were examined by assessing eNOS, iNOS, HO-1 and COX-2 expression in whole-kidney lysates by Western immunoblotting, and cellular colocalization of these enzymes was determined using immunofluorescence microscopy. Results:Three weeks of opioid treatment resulted in increased kidney weight, elevated BUN and proteinuria, and decreased MAP. This was accompanied by histological abnormalities including glomerular enlargement, hypercellularity, peritubular congestion, vasodilatation and tubular casts. The vasoregulatory molecules iNOS, eNOS, HO-1 and COX-2 were upregulated in the kidneys. The NOS inhibitor L-NAME prevented the morphine-induced increase in perfusion and kidney weight. Conclusions: The chronic use of clinically relevant doses of opioidsleads to structural kidney abnormalities, upregulates NOS, COX-2 and HO-1, and results in renal dysfunction in a murine model of cancer.
Journal Section:
Original Paper
References
1.
Lameire NH, Flombaum CD, Moreau D, Ronco C: Acute renal failure in cancer patients. Ann Med 2005;37:13–25.
[PubMed]
2.
Joerger M, Schellens JH, Beijnen JH: Therapeutic drug monitoring of non-anticancer drugs in cancer patients. Methods Find Exp Clin Pharmacol 2004;26:531–545.
[PubMed]
3.
Kapusta DR, Sezen SF, Chang JK, Lippton, H, Kenigs, VA: Diuretic and antinatriuretic responses produced by the endogenous opioid-like peptide, nociceptin (orphanin FQ). Life Sci 1997;60:PL15–PL21.
4.
Kapusta DR, Kenigs VA: Cardiovascular and renal responses produced by central orphanin FQ/nociceptin occur independently of renal nerves. Am J Physiol 1999;277:R987–R995.
5.
Shirasaka T, Kunitake, T, Kato K, Takasaki M, Kannan H: Nociceptin modulates renal sympathetic nerve activity through a central action in conscious rats. Am J Physiol 1999;277:R1025–R1032.
6.
Rao TK, Nicastri AD, Friedman EA: Natural history of heroin-associated nephropathy. N Engl J Med 1974;290:19–23.
[PubMed]
7.
Ahmadi J, Benrazavi L: Substance use among Iranian nephrologic patients. Am J Nephrol 2002;22:11–13.
[PubMed]
8.
Kilcoyne MM, Gocke DJ, Meltzer JI, Daly JJ, Thomson GE, Hsu KC, Tannenbaum M: Nephrotic syndrome in heroin addicts. Lancet 1972;1:17–20.
[PubMed]
9.
Dettmeyer RB, Preuss J, Wollersen H, Madea B: Heroin-associated nephropathy. Expert Opin Drug Saf 2005;4:19–28.
[PubMed]
10.
do Sameiro Faria M, Sampaio S, Faria V, Carvalho E: Nephrology associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003;18:2308–2313.
[PubMed]
11.
Singhal PC, Gibbons N, Abramovici M: Long term effects of morphine on mesangial cell proliferation and matrix synthesis. Kidney Int 1992;41:1560–1570.
[PubMed]
12.
Singhal PC, Abramovici M, Bansal M, Jaffer S, Mattana J, Shah R, Gibbons N: Opioids modulate migration, spreading and adherence of mesangial cells. Nephron 1994;68:366–371.
[PubMed]
13.
Singhal PC, Sharma P, Gibbons N, Franki N, Kapasi A, Wagner JD: Effect of morphine on renomedullary interstitial cell proliferation and matrix accumulation. Nephron 1997;77:225–234.
[PubMed]
14.
Singhal PC, Sharma P, Sanwal V, Prasad A, Kapasi A, Ranjan R, Franki N, Reddy K, Gibbons N: Morphine modulates proliferation of kidney fibroblasts. Kidney Int 1998;53:350–357.
[PubMed]
15.
Singhal PC, Sagar S, Reddy K, Sharma P, Ranjan R, Franki N: HIV-1 gp120 envelope protein and morphine-tubular cell interaction products modulate kidney fibroblast proliferation. J Investig Med 1998;46:243–248.
[PubMed]
16.
Flores O, Camera LA, Hergueta A, Gallego B, Perez Barriocanal F, Gutkowska J, Lopez Novoa JM: Role of atrial natriuretic factor, hemodynamic changes and renal nerves in the renal effects of intraperitoneal morphine in conscious rats. Kidney Blood Press Res 1997;20:18–24.
[PubMed]
17.
Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, Casares F, Goligorsky MS: Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem 1995;270:30290–30293.
[PubMed]
18.
Poonawala T, Levay-Young BK, Hebbel RP, Gupta K: Opioids heal ischemic wounds in the rat. Wound Repair Regen 2005;13:165–174.
[PubMed]
19.
Abraham NG, Kappas A: Heme oxygenase and the cardiovascular-renal system. Free Radic Biol Med 2005;39:1–25.
[PubMed]
20.
Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002;62:4491–4498.
[PubMed]
21.
Chen C, Farooqui M, Gupta K: Morphine stimulates VEGF-like signaling in mouse retinal endothelial cells. Current Neurovasc Res 2006;3:171–180.
22.
Patel J, Manjappa N, Bhat R, Mehrotra P, Bhaskaran M, Singhal PC: Role of oxidative stress and heme oxygenase activity in morphine-induced glomerular epithelial cell growth. Am J Physiol Renal Physiol 2003;285:F861–F869.
23.
Ramnaraine M, Pan W, Goblirsch M, Lynch C, Lewis V, Orchard P, Mantyh P, Clohisy DR: Direct and bystander killing of sarcomas by novel cytosine deaminase fusion gene. Cancer Res 2003;63:6847–6854.
[PubMed]
24.
Weibel ER, Gomez DM. A principle for counting tissue structures on random sections. J Appl Physiol 1962;17:343–348.
[PubMed]
25.
Osborn JW: Hypothesis: Set-points and long-term control of arterial pressure. A theoretical argument for a long-term arterial pressure control system in the brain rather than the kidney. Clin Exp Pharmacol Physiol 2005;32:384–393.
[PubMed]
26.
Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U: Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model. J Biosci 2005;30:245–252.
[PubMed]
27.
Daskalakis N, Winn MP: Focal and segmental glomerulosclerosis. Cell Mol Life Sci 2006;63:2506–2511.
[PubMed]
28.
Abbate M, Zoja C, Remuzzi G: How does proteinuria cause progressive renal damage? J Am Soc Nephrol 2006;17:2974–2984.
[PubMed]
29.
Koopman RJ, Mainous AG 3rd, Liszka HA, Colwell JA, Slate EH, Carnemolla MA, Everett CJ: Evidence of nephropathy and peripheral neuropathy in US adults with undiagnosed diabetes. Ann Fam Med 2006;4:427–432.
[PubMed]
30.
Hill SA, Quinn K, Shelly MP, Park GR: Reversible renal failure following opioid administration. Anaesthesia 1991;46:938–939.
[PubMed]
31.
Patel J, Manjappa N, Bhat R, Mehrotra P, Bhaskaran M, Singhal PC: Role of oxidative stress and heme oxygenase activity in morphine-induced glomerular epithelial cell growth. Am J Physiol Renal Physiol 2003;285:F861–F869.
32.
Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE: Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111:707–716.
[PubMed]
33.
Camici M: Renal glomerular permselectivity and vascular endothelium. Biomed Pharmacother 2005;59:30–37.
[PubMed]
34.
Molitoris BA, Sutton TA: Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 2004;66:496–499.
[PubMed]
35.
Nasrallah R, Hebert RL: Prostacyclin signaling in the kidney: implications for health and disease. Am J Physiol Renal Physiol 2005;289:F235–F246.
36.
Baylis C, Harton P, Engels K: Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol 1990;1:875–881.
[PubMed]
37.
Krier JD, Romero JC: Systemic inhibition of nitric oxide and prostaglandins in volume-induced natriuresis and hypertension. Am J Physiol 1998;274:R175–R180.
38.
Costa MA, Elesgaray R, Loria A, Balaszczuk AM, Arranz C: Vascular and renal effects of dopamine during extracellular volume expansion: Role of nitric oxide pathway. Life Sci 2006;78:1543–1549.
[PubMed]
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