Rolf A.K. Stahl

Morphine Modulates Mesangial Immunoglobulin G Uptake in Rats with Antithymocyte Serum-Induced Mesangial Cell Injury

The glomerular mesangium is an important site of activity in patients with heroin addiction. We studied the effect of morphine, a metabolite of heroin, on the mesangial immunoglobulin G aggregate uptake in a model of specific mesangial cell injury. Isolated specific mesangial cell injury was developed in Lewis rats by injecting intravenously antithymocyte serum (ATS). Forty-eight hours later, radioiodinated, heat aggregated immunoglobulin G (AHIgG125I) was administered (20 mg/100 g i.v.) by tail vein. At 4 and 24 h, kidneys, liver, and spleen were removed, glomeruli isolated, and the radioactivity measured. Blood levels of AHIgG125I were measured at 0, 4 and 24 h. For ultrastructural studies, IgG-coated gold particles were injected, and the mesangial circulation was studied. At 4 h, ATS-treated rats showed a lower (p < 0.02) accumulation of AHIgG125I in the mesangium when compared with control rats (controls 511,012 +/- 10,807 vs. ATS 464,614 +/- 7,944 cpm/g glomerular protein). ATS plus morphine treated rats showed a higher (p < 0.01) accumulation of of AHIgG125I when compared with rats treated with AS alone. Even at 24, h morphine-treated ATS rats showed a higher accumulation of AHIgG125I when compared with those treated with ATS alone. Ultrastructural studies showed aggregation of IgG-coated gold particles in the mesangial cell endolysosomes of control rats. Our results suggest that macromolecules may dwell longer in the mesangium of rats with intact mesangial cells. This increase in transit time may be related to the uptake of these macromolecules by mesangial cells. Morphine seems to enhance the accumulation of macromolecules in the mesangium, independent of its action on mesangial cells.

Thromboxane mediates glomerular haemodynamics in a model of chronic glomerular disease.

Abstract. In order to evaluate a possible haemodyna‐mic role of cyclooxygenase products in chronic renal disease, a model of chronic glomerular injury was induced in nephritic rats by unilateral nephrectomy and high dietary protein intake. Eight weeks after induction of an in situ immune complex glomerulo‐nephritis (ICGN), rats subjected to high protein (HP) intake (42% protein) and uninephrectomy revealed a significantly lower glomerular filtration rate (GFR; 485±53 μ1 min‐1 100 g‐1 body weight (BW)) compared with uninephrectomized rats with ICGN which were on low protein (LP) diet (6% protein) (825 ±155 μ1 min‐1 100 g‐1 BW) (P<0.01). The glomerular thromboxane B2 (TxB2) formation in uninephrectomized rats with ICGN on either LP or HP intake was not significantly different (HP: 473 ± 61; LP: 493 ± 63 pg mg‐1 min‐1), but was significantly higher when compared with non‐nephritic controls on either diet. Glomerular prostaglandin E2 (PGE2) production in rats on HP diet was higher compared with rats with LP intake (HP: 617 ± 67; LP: 351±76 pg mg‐1 min‐1) (P<0.01). The thromboxane receptor blocker daltro‐ban significantly elevated suppressed GFR in ICGN rats on HP diet (ICGN + vehicle: 426± 69; ICGN + daltro: 689 + 66 μ1 min‐1 100 g‐1 BW) (P<0.01). Thromboxane receptor blockade had no effect on glomerular haemodynamics in ICGN animals receiving LP diet (ICGN + vehicle: 771 ± 24; ICGN + daltro: 684+85 μ1 min‐1 100 g‐1 BW). The cyclooxygenase inhibitor indomethacin reduced the already compromised GFR in ICGN animals on HP diet (ICGN + vehicle: 533±54; ICGN + indo: 335±43 μl min‐1 100 g‐1BW) (P<0.05), but was without effect on GFR in nephritic rats on LP intake (ICGN + vehicle: 785±102; ICGN + indo: 633 ± 89 μl min‐1 100 g‐1 BW). These data demonstrate that eicosanoids modulate glomerular haemodynamics in a model of chronic glomerular disease induced by immune complex formation, uninephrectomy and HP intake.

The Role of Eicosanoids in Glomerular Immune Injury

The characteristic features of several models of experimental glomerular immune injuries are reduction of the glomerular filtration rate and loss of the permselectivity of the glomerular filtration barrier, with the appearance of proteinuria [1]. These alterations are, in most cases, the consequence of glomerular antibody binding, immune complex formation, activation of mediator systems, and the glomerular infiltration of inflammatory cells (polymorphonuclear neutrophils (PMNs), monocytes, and platelets) [2]. In this initial process of experimental glomerular injuries, formation of eicosanoids in whole isolated glomeruli is enhanced [3–6].