Endotoxin-Mediated Changes in Plasma Endothelin Concentrations, Renal Endothelin Receptor and Renal Function

Abstract

The purpose of these studies was to examine the changes in renal endothelin (ET) receptor, renal function and plasma ET (ET-1) concentration in male Sprague-Dawley rats injected with nonlethal doses of Escherichia coli endotoxin (LPS). Prior to the injection of LPS, kidney ET receptor density was 59 ± 5 fmol/mg protein (n = 20). At 24 h after the injection of 1 or 3 mg/kg LPS, [¹²⁵I]ET-1 binding to kidney membranes was increased by 70% in both LPS groups (p < 0.001). Scatchard analysis of the saturation binding experiments confirmed that the increase in [¹²⁵I]ET-1 binding was due to an increase in receptor density with no change in affinity (202 pmol/l at baseline and 168 pmol/l and 246 pmol/l at 24 h after the injection of 1 and 3 mg/kg LPS, respectively). At 7 days after the injection of LPS, kidney ET-1 receptor density was still increased by 30 ± 5% and 58 ± 16%, respectively (p < 0.05, compared to the baseline value). Baseline values for Na⁺ and K⁺ excretion were approximately 115 µEq/h and 214 ± µEq/h respectively, and were decreased with LPS. Maximal decreases in Na⁺ and K⁺ excretion occurred at 48 h (-85%) and 30 h (–82%), respectively, following the injection of 3 mg/kg LPS and returned to baseline levels in 7 days. Following the injection of 3 mg/kg LPS, plasma immunoreactive ET-1, as measured by radioimmunoassay, increased in a time-dependent manner: the maximal increase of 60% occurred within 1 h after the injection of LPS (p < 0.05), and thereafter returned to baseline levels. Kidney tissue levels of ET-1 increased from baseline values of 2.6 fmol/mg protein to a peak of 4.6 fmol/mg protein 1 h after the injection of LPS. Tissue ET-1 levels were still significantly elevated at 6 h but not 24 h after LPS injection. These studies suggest that ET-1, either by increases in plasma concentration and/or altered receptor density, may be involved in the LPS-induced impairment of renal function.

Effect of endotoxin on the angiotensin II receptor in cultured vascular smooth muscle cells

“…Nevertheless, the observation that LPS does not increase vasopressin binding in SMC indicates the existence of some specificity. In accordance with our results, an increased number of endothelin receptors has recently been found in kidneys of endotoxaemic rats (Nambi et al, 1991). The reason why some receptors are induced by LPS while others are not, may simply reflect the fact that different genes may be regulated in different ways by the same substance.…”

Acute endotoxemia in rats induces down-regulation of V2 vasopressin receptors and aquaporin-2 content in the kidney medulla

“…This effect was dependent on nitric oxide production for type 1 angiotensin II receptors in messangial cells [44], while the reduction in a-adrenergic and V1a vasopressin receptors was nitric oxide independent [43,46]. The receptor down-regulation observed in the present study and former reports is unlikely to reflect a general inhibitory effect due to non-specific membrane alterations, since LPS injection has been shown to increase renal endothelin receptors [47,48].…”

Ablation of Transient Receptor Potential Vanilloid 1 Abolishes Endothelin-Induced Increases in Afferent Renal Nerve Activity

“…In normal rats, the plasma ET-1 level is at 28 ± 3 fmol/ml, whereas the ET-1 concentration in the urine is about 4.7 ± 0.3 pmol/24h and in the kidney tissue 2.6 fmol/mg protein24, 25. Evidence shows that little circulating ET-1 is excreted into the urine, and the most urinary ET is renal origin26.…”