Stephan Segerer

Renal injury in apolipoprotein E-deficient mice.

Hyperlipidemia is thought to accelerate the progression of renal diseases, but the mechanisms by which hyperlipidemia exerts its deleterious effect is still poorly understood. The aim of this study was to describe the renal pathology in a hyperlipidemic mouse strain, the apolipoprotein E–deficient mice (apoE−/−). Renal specimens from a total of 34 mice were studied, including 19 apoE−/− females at the age of 36 weeks, 9 apoE−/− females at the age of 24 weeks, and 6 wild-type females (C57BL/6) as controls. Kidneys were evaluated by histologic examination, immunohistochemistry, and electron microscopy. Immunohistochemistry was used to detect MAC-2–expressing monocyte/macrophages, and the proliferation marker PCNA. Glomerular cell number, glomerular matrix area, and glomerular area were quantified by morphometry. Glomerular lesions in apoE−/− mice were characterized by macrophage accumulation, commonly with foam cell appearance, deposition of extracellular matrix, glomerular hyperplasia, and at times prominent mesangiolysis associated with capillary microaneurysms. Some cases demonstrated lipid deposits filling glomerular capillaries. Arterioles of the vascular pole demonstrated a “foamy” degeneration of smooth muscle cells. These lesions related to hyperlipidemia in this well-established mouse strain have not been previously described. Because this mouse strain is among the most widely studied for interventions aimed at altering hyperlipidemia and the progression of atherosclerosis, we believe that our observations may be of major importance for the accurate interpretation of interventional studies in this strain and offer a new opportunity to study mechanisms of hyperlipidemic renal injury.

Cryoglobulinemic Glomerulonephritis in Thymic Stromal Lymphopoietin Transgenic Mice

Mixed cryoglobulins are complexes of immunoglobulins that reversibly precipitate in the cold and lead to a systemic disease in humans. Renal involvement usually manifests as a membranoproliferative glomerulonephritis with marked monocyte infiltration and, at times, intracapillary thrombi. Thymic stromal lymphopoietin (TSLP) is a recently cloned cytokine that supports differentiation and long-term growth of B cells. Here we report that TSLP overexpression in mice results in the development of mixed cryoglobulins, with renal involvement closely resembling cryoglobulinemic glomerulonephritis as it occurs in humans. One hundred twenty-three mice were sacrificed at monthly intervals, with at least five TSLP transgenic mice and five controls in each group. Blood, kidneys, spleen, liver, lung, and ear were collected and studied by routine microscopy, immunofluorescence, immunohistochemistry, and electron microscopy. TSLP transgenic animals developed polyclonal mixed cryoglobulinemia (type III) and a systemic inflammatory disease involving the kidney, spleen, liver, lung, and ears. Renal involvement was of a membranoproliferative type demonstrating thickened capillary walls with cellular interposition and double contours of the basement membrane, expansion of the mesangium because of increased matrix and accumulation of immune-deposits, subendothelial immune-deposits, focal occlusion of capillary loops, and monocyte/macrophage influx. In contrast to the severe glomerular lesions, the tubulointerstitium was not involved in the disease process. The renal lesions and the disease course were more severe in females when compared to males. We describe a mouse strain in which a B-cell-promoting cytokine leads to formation of large amounts of mixed cryoglobulins and a systemic inflammatory injury that resembles important aspects of human cryoglobulinemia. This is the first reproducible mouse model of renal involvement in mixed cryoglobulinemia, which enables detailed studies of a membranoproliferative pattern of glomerular injury.

Enhanced expression of Duffy antigen in the lungs during suppurative pneumonia.

Duffy antigen is a chemokine binding protein expressed on the surface of erythrocytes and postcapillary venular endothelial cells. It binds selective CXC and CC chemokines with high affinity. Although Duffy antigen is present in the normal pulmonary vascular bed, it is not known whether its expression is altered by innate inflammatory responses in the lungs. We studied Duffy antigen expression by immunohistochemistry in autopsy lung specimens from 16 cases of suppurative pneumonia, 11 cases of acute lung injury, and seven normal lungs. In lungs with suppurative pneumonia, Duffy antigen was expressed in higher numbers of pre- and postcapillary parenchymal vessels compared to normal specimens or specimens with acute lung injury (p<0.03 and p<0.02, respectively). Lungs with suppurative pneumonia also showed Duffy antigen expression on the alveolar septa, whereas this was a rare finding in normal specimens or in acute lung injury (p<0.02). Furthermore, Duffy antigen labeling of the alveolar septa localized to regions with airspace accumulation of neutrophil-rich exudates. In summary, Duffy antigen expression is increased in the vascular beds and alveolar septa of the lung parenchyma during suppurative pneumonia, suggesting that Duffy antigen may have a functional role in the lung parenchyma during inflammation.