Glomerular and Renal Vascular Structural Changes in α8 Integrin-Deficient Mice

Abstract

Abstract. Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the ␣8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. ␣8-deficient (␣8Ϫ/Ϫ) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of ␣8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of ␣8Ϫ/Ϫ mice would be completely normal. Therefore, the renal phenotype of adult ␣8Ϫ/Ϫ mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. ␣8Ϫ/Ϫ mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and ␣8Ϫ/Ϫ mice. Quantitative morphologic analyses revealed that the glomeruli of ␣8Ϫ/Ϫ mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the ␣8 ligand fibronectin) was expanded in ␣8Ϫ/Ϫ mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of ␣8Ϫ/Ϫ mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor ␣2 integrin in ␣8Ϫ/Ϫ mice. The glomerular capillary length density was significantly greater in ␣8Ϫ/Ϫ mice than in wild-type mice. Cortical arterial vessel walls were not altered in ␣8Ϫ/Ϫ mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of ␣8, glomerular and renal vascular alterations in ␣8Ϫ/Ϫ mice were relatively mild. Only aged ␣8Ϫ/Ϫ mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of ␣8 can be largely compensated for, at least in younger ␣8Ϫ/Ϫ mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor ␣2 contribute to maintaining the glomerular structure in ␣8Ϫ/Ϫ mice. The compensatory mechanisms involved will be the subject of future research.Integrins are heterodimeric transmembrane glycoproteins, each consisting of two noncovalently linked chains, the ␣ and ␤ subunits. Eighteen ␣ and eight ␤ chains have been identified; they combine to form 24 integrin receptor types (1). Cellmatrix interactions mediated mainly by integrins of the ␤1 family play important roles in embryogenesis and maintenance of the normal structure and function of organs, including the kidney (1). Furthermore, many human and experimental renal diseases are associated with altered expression of integrins (2), pointing to an important role for integrins in the development and/or progress...

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