endothelin-1 and Lupus-Nephritis

Our study aims to evaluate the endothelial cell-podocyte crosstalk in proliferative lupus nephritis (LN). The semi-quantification scores of glomerular endothelial cell injury and the foot process width (FPW) were processed in 110 proliferative LN patients. Podocytes were stimulated with LN-derived IgG. Glomerular endothelial cells were treated with podocyte-conditioned medium (PCM), and then podocytes were incubated with endothelial cell-conditioned medium (ECM). The levels of vascular endothelial growth factor-A (VEGF-A) in PCM and endothelin-1 in ECM were analyzed, and the injury of podocyte and glomerular endothelial cells were further evaluated. The pathological score of glomerular endothelial cell injury was correlated with FPW in LN complicated with thrombotic microangiopathy. In vitro study showed the following: 1. Stimulation of podocytes by IgG from LN led to decline in the expression of nephrin with cytoskeleton rearrangement, and reduction of VEGF-A levels. 2. Exposure of glomerular endothelial cells to PCM incubated with LN-derived IgG (PCM-LN) induced more endothelin-1 secretion and disruption of intercellular tight junction. 3. Exposure of podocytes to ECM stimulated with PCM-LN could induce cytoskeleton redistribution with decrease of nephrin. In conclusion, the pathological glomerular endothelial cell lesions were associated with FPW and the VEGF-endothelin-1 system might play a critical role in the endothelial cell-podocyte crosstalk in LN.

Topics: Adult; Biopsy; Case-Control Studies; Cells, Cultured; Endothelial Cells; Endothelin-1; Female; Humans; Immunohistochemistry; Kidney; Kidney Glomerulus; Lupus Nephritis; Male; Podocytes; Receptor Cross-Talk; Vascular Endothelial Growth Factor A; Young Adult

Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 +/- 2.7%, 10.0 +/- 3.0 pg/mumol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 +/- 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.

Topics: Adult; Aged; Biomarkers; Endothelin-1; Female; Humans; Inflammation; Kidney Failure, Chronic; Lupus Nephritis; Male; Middle Aged; Young Adult

To investigate the relationship between plasma endothelin(ET), nitric oxide(NO) levels and, renal hypertension and renal function.. The plasma concentration of ET-1 was detected by immunofluorescence assay. The plasma concentration of NO was detected by biochemistry assay.. 1. In renal disease patients, plasma concentration ET-1 was markedly elevated, and plasma concentration of NO was decreased, compared with the healthy subjects(P < 0.01). 2. Plasma concentration of ET-1 was markedly increased and plasma concentration of NO was decreased in the patients with renal hypertension. 3. Plasma level of ET-1 was higher, and plasma level of NO was lower in the patients with renal function damage than that of those without renal function damage. 4. BP, BUN and Scr were positively correlated with plasma ET-1, but they were negatively correlated with plasma concentration of NO.. Plasma ET-1 and NO may play an important role in pathogenesis of renal hypertension; the change of their levels may be related to the progress of these renal diseases.

Topics: Adult; Chronic Disease; Endothelin-1; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Function Tests; Lupus Nephritis; Male; Middle Aged; Nitric Oxide

To understand better the function of endothelin-1 (ET-1) in renal physiology, we examined vascular and glomerular expression of ET-1 in normal human kidney and in lupus nephritis. Immunohistochemical analysis revealed that renal endothelium of glomeruli, arteries, veins, and capillaries expressed ET-1. Endothelial cells were the principal source of glomerular ET-1; positive immunostaining was detected only rarely in mesangial cells and vascular smooth muscle cells from normal kidney. However, mesangial staining for ET-1 was elevated in patients with lupus nephritis, suggesting that under certain conditions mesangial cells elaborate ET-1. Indeed cultured human mesangial cells from normal subjects secreted ET-1 peptide. ET-1 secretion was augmented by the protein kinase C activator phorbol ester and by transforming growth factor-beta1 (TGF-beta1), a cytokine implicated in the development of glomerulosclerosis. Transient transfection of cultured mesangial cells with a preproET-1 reporter construct showed that the preproET-1 promoter is transcriptionally active in mesangial cells and is stimulated by TGF-beta1, phorbol ester, or ectopic expression of protein kinase beta1. Cultured human mesangial cells have both ETA and ETB receptors that contribute to ET-1-stimulated mitogenesis. Taken together, these results demonstrate that ET-1 is expressed at sites where paracrine or autocrine signaling by ET-1 might control renal vasoconstriction, glomerular filtration rate, and remodeling of the glomerulus in renal disease.

Topics: Cells, Cultured; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Glomerular Mesangium; Humans; Kidney Glomerulus; Lupus Nephritis; Muscle, Smooth, Vascular; Polymerase Chain Reaction; Protein Kinase C; Recombinant Proteins; Renal Circulation; RNA, Messenger; Tetradecanoylphorbol Acetate; Transcription, Genetic; Transfection; Transforming Growth Factor beta