Distribution of the major histocompatibility complex antigens in human and rat kidney

Distribution of the major histocompatibility complex antigens in human and rat kidney. We have compared the distribution of the major histocompatibility complex (MHC) antigens in human and rat kidney using monospecific antisera to class I and II antigens of the MHC. FITC/TRITC double immunofluorescence was used to demonstrate these antigens in frozen sections and the Staphylococcus aureus Cowan I rosette assay on the cell surface. In both species, the MHC antigens were prominently present on the passenger leukocytes. Immunofluorescence analysis of human kidney demonstrated that the class I, β2-microglobulin (β2m), and class II antigens were present in the vascular endothelial cells and class I antigens in the renal tubular cells. The Staphylococcus assay demonstrated that these antigens were also exposed on the respective cell surfaces. In clear contrast, in the rat, class I, the β2m, and class II antigens were absent from the kidney vascular endothelium of large vessels and intertubular capillaries; however, large amounts of class II antigens were seen inside the proximal renal tubular cells. The Staphylococcus assay indicated that none or very little of these antigens were exposed on the kidney parenchymal cell surface. These differences may explain why rat renal transplants are relatively non-immunogenic and easily accepted, whereas human renal transplant recipients must be immunosuppressed ad infinitum.Distribution des antigènes du complexe d'histocompatibilité principal du rein d'homme et de rat. Nous avons comparé la distribution des antigènes du complexe d'histocompatibilité principal (MHC) dans du rein d'homme et de rat en utilisant des antisérums monospécifiques des antigènes des classes I et II du MHC. Une double immunofluorescence FITC/TRITC a été utilisée pour démontrer ces antigènes dans des sections congelées et le dosage des rosettes de Staphylocoque doré Cowan I pour les démontrer à la surface cellulaire. Dans les deux espèces, les antigènes MHC étaient essentiellement présents sur les leucocytes de passage. L'analyse en immunofluorescence de rein humain a démontré que les antigènes de classe I, 1 β2-microglobuline (β2m) et de classe II étaient présents dans les cellules endothéliales vasculaires, et ceux de classe I dans les cellules tubulaires rénales. Le dosage Staphylocoque a démontré que ces antigènes étaient également exposés sur les surfaces cellulaires respectives. De facon clairement opposée, chez le rat, les antigènes de classe I, 1 β2m et de classe II étaient absents de l'endothélium vasculaire rénal des gros vaisseaux et des capillaires intertubulaires; cependant, de grandes quantités d'antigènes de classe II étaient visibles à l'intérieur des cellules tubulaires rénales proximales. L'essai Staphylocoque a indiqué qu'aucun ou très peu de ces antigènes étaient exposés à la surface des cellules parenchymateuses rénales. Ces différences pourraient expliquer pourquoi les greffons rénaux de rat sont relativement non immunogènes et facilement tolérés, alors que les receveurs de transplants rénaux humains doivent être immunodéprimés indéfiniment

Urine neutrophil gelatinase-associated lipocalin is a marker of graft recovery after kidney transplantation

Delayed graft function (DGF), especially long-lasting DGF, complicates kidney transplant outcome. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute kidney injury marker; therefore, we tested whether urine NGAL could predict DGF, prolonged DGF (lasting over 14 days), or the quality of kidney function in transplant recipients without DGF (non-DGF). We collected urine samples from 176 recipients transplanted with deceased donor kidneys before and various days after transplantation. A total of 70 transplantations had DGF, of which 26 were prolonged. Patients who developed DGF had a significantly slower decrease in urinary NGAL compared with those without DGF, such that day 1 NGAL predicted DGF (area under the curve (AUC) 0.75) and predicted DGF in 15 of 112 cases with day 1 urine output over 1l (AUC 0.70) and in 19 of 86 cases with a day 1 decrease in creatinine over 50μmol/l (AUC 0.74). The urinary NGAL level on day 1 predicted prolonged DGF (AUC 0.75), which had significantly worse 1-year graft survival (73%), compared with shorter DGF (100%). In non-DGF, high day 3 NGAL (greater than the mean) was associated with significantly worse kidney function at 3 weeks compared with low NGAL, but not at 3 months and 1 year. NGAL did not correlate with long-term function in DGF. Hence, day 1 urinary NGAL predicted DGF even when it was not clinically expected early on, and importantly, it predicted prolonged DGF that led to worse graft survival

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFβ1, collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways