Unveiling mesangial mysteries

Abstract

The intercapillary mesangial cells are eager participants in fibrotic injury to the glomerulus, and indeed they appear in many instances to be the primary, if not sole, culprits. Once provoked, mesangial cells proliferate and exude large amounts of extracellular matrix, which narrows and, in severe cases, obliterates glomerular capillary lumens. Despite their major importance in several glomerulopathies, however, many mysteries surround the mesangial cells and their associated extracellular matrices. Among others, these mysteries include embryonic origins of mesangial cells during kidney organogenesis, regulation of their entry into and exit from the mitotic and migratory cycles, composition and structure of the mesangial matrix, and controls for synthesis and turnover of this matrix. The paper in this issue of Kidney International by Hansen and Abrass [1.Hansen K. Abrass C.K. Laminin-8/9 is synthesized by rat glomerular mesangial cells and is required for PDGF-induced mesangial cell migration.Kidney Int. 2003; 64: 110-118Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] sheds much needed light on some of these mysteries. The lineage(s) of mesangial cells has been a challenging problem to address squarely, in part because of the relative paucity of markers that discriminate developing mesangial cells specifically. Nevertheless, immunohistologic studies carried out more than a decade ago on fetal human kidney tissue strongly suggested that platelet-derived growth factor-B (PDGF-B) originating from immature podocytes may engage its receptor, PDGFRβ, which is displayed on a variety of vascular and interstitial cells (including mesangial progenitors), resulting in the recruitment of cells into developing glomeruli and establishment of the mesangium [2.Alpers C.E. Seifert R.A. Hudkins K.L. et al.Developmental patterns of PDGF B-cahin, PDGF-receptor, and alpha-actin expression in human glomerulogenesis.Kidney Int. 1992; 42: 390-399Abstract Full Text PDF PubMed Scopus (110) Google Scholar]. Functional evidence that this ligand/receptor signaling system is important for mesangial formation and stabilization came from gene targeting studies in mice. When genes encoding either PDGF-B or PDGFRβ are deleted, mice die perinatally and renal glomeruli consist of greatly dilated capillary loops with absent mesangia [3.Soriano P. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice.Genes Dev. 1994; 8: 1888-1896Crossref PubMed Scopus (756) Google Scholar, 4.Leveen P. Pekny M. Gebre-Medhin S. et al.Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities.Genes Dev. 1994; 8: 1875-1887Crossref PubMed Scopus (820) Google Scholar]. More recently, immunohistochemical labeling of embryonic rat kidneys with anti-Thy1.1 (mesangial cell marker in adult rats) and anti-RECA-1, anti-PECAM (CD31), and anti-Flk-1 (all endothelial markers) showed that mesangial and glomerular endothelial cells appear to be derived from a common, metanephric mesenchymal precursor pool [5.Ricono J.M. Xu Y. Arar M. et al.Morphological insights into the origin of glomerular endothelial and mesangial cells and their precursors.J Histochem Cytochem. 2003; 51: 141-150Crossref PubMed Scopus (43) Google Scholar]. As these vascular primordia invade the glomerular vascular cleft, they subsequently differentiate into mesangial and endothelial cells, respectively, and adopt their unique phenotypes. Although these cells may indeed share a common forerunner, the full mechanisms accounting for their attraction and specification within the glomerulus still remain elusive. Lined on their inner surfaces by slender endothelial cells perforated by innumerable open fenestrae, and covered on outer surfaces by podocytes with unique, interdigitating foot processes, the glomerular capillaries are the most unusual vascular structures in the body. During glomerular development, various laminin and type IV collagen isoforms appear and then disappear as the glomerular basement membrane (GBM) undergoes assembly and maturation. Although the reasons for these isoform transitions are not understood, mice that lack laminin α5 [6.Miner J.H. Li C. Defective glomerulogenesis in the absence of laminin alpha 5 demonstrates a developmental role for the kidney glomerular basement membrane.Dev Biol. 2000; 217: 278-289Crossref PubMed Scopus (212) Google Scholar] and β2 [7.Noakes P.G. Miner J.H. Gautum M. et al.The renal glomerulus of mice lacking s-laminin/laminin β2: Nephrosis despite molecular compensation by laminin β1.Nat Gen. 1995; 10: 400-406Crossref PubMed Scopus (342) Google Scholar] chains (components of laminin-11 found in GBMs of fully mature glomeruli) fail to develop normal glomeruli and die. Similarly, mice with mutant collagen α3 (IV) [part of the collagen α3 (IV), α4 (IV), α5 (IV) heterotrimer typical of mature GBM] are also abnormal, develop GBMs that resemble those seen in humans with Alport disease, and these mice, too, succumb to renal failure [8.Miner J.H. Sanes J. Molecular and functional defects in kidneys of mice lacking alpha collagen 3 (IV): Implications for Alport syndrome.J Cell Biol. 1996; 135: 1403-1413Crossref PubMed Scopus (235) Google Scholar, 9.Cosgrove D. Meehan D.T. Grunkemeyer J.A. et al.Collagen COL4A3 knockout: A mouse model for autosomal Alport syndrome.Genes Dev. 1996; 10: 2981-2992Crossref PubMed Scopus (276) Google Scholar, 10.Lu W. Phillips C.L. Killen P.D. et al.Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome.Genomics. 1999; 61: 113-124Crossref PubMed Scopus (60) Google Scholar]. Basement membrane isoform transitions therefore appear to be important for acquisition and/or maintenance of the highly differentiated state achieved by glomerular endothelial cells and podocytes. How isoforms expressed early during glomerulogenesis are removed from the GBM, and how isoforms found later in glomerular development are added, are not known. The mesangial matrix bears certain similarities to the GBM but is nevertheless distinct in both structure and composition. Unlike the GBM (and most other basal laminae), the mesangial matrix lacks defined areas of compacted matrix and is organized into a looser meshwork. Although it contains the same family of matrix molecules as the GBM, the mesangium apparently does not undergo isoform transitioning as extensively, and instead contains a profile of laminins and collagen IV commonly found in immature GBMs. Specifically, mesangial matrices in most adult mammalian species contain laminin-1 (and -2 in humans and mice but -4 in rats) and α1 (IV) and α2 (IV) collagen [11.Miner J.H. Renal basement membrane components.Kidney Int. 1999; 56: 2016-2024Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar], and therefore are similar to GBMs found in immature glomeruli. Mature GBMs, on the other hand, include laminin-11 and α3, α4, α5 (IV) collagen, as mentioned earlier. The paper by Hansen and Abrass [1.Hansen K. Abrass C.K. Laminin-8/9 is synthesized by rat glomerular mesangial cells and is required for PDGF-induced mesangial cell migration.Kidney Int. 2003; 64: 110-118Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] adds importantly to our limited understanding of the mesangium for several reasons. First, these investigators provide evidence that cultured mesangial cells (but not cultured glomerular endothelial or epithelial cells) synthesize laminin α4 chain, a component of the laminin 8 and/or 9 isoform important for stability of capillary basement membranes [12.Thyboll J. Kortesmaa J. Cao R. et al.Deletion of the laminin α4 chain leads to impaired microvessel maturation.Mol Cell Biol. 2002; 22: 1194-1202Crossref PubMed Scopus (242) Google Scholar]. Further, they show that antibodies immunolocalize laminin α4 to these same cells in culture, as well as to mesangial areas of mature rats in vivo. This particular laminin chain has previously been seen in mesangial areas of immature, but not mature, mice [13.Miner J.H. Patton B.L. Lentz S.I. et al.The laminin α chains: Expression, developmental transitions, and chromosomal locations of α1–5, identification of heterotrimeric laminins 8–11, and cloning of a novel α3 isoform.J Cell Biol. 1997; 137: 685-701Crossref PubMed Scopus (565) Google Scholar]. The localization of this chain to the mesangium in adult rats may therefore reflect a species difference or be attributable to differences in the antibodies used in the separate studies. Importantly, this paper also shows that laminin-8/9 purified from cultured mesangial cells promoted fewer vinculin- and talin-containing focal adhesions in cultured mesangial cells. Finally, these authors showed in an in vitro assay that antibodies against laminin α4 completely blocked PDGF-induced mesangial cell migration. In summary, the paper identifies a new component of the mesangial matrix, laminin-8/9, and further suggests that mesangial cells may utilize this laminin isoform specifically during PDGF-stimulated migration in vivo. These interrelationships may therefore be of critical importance during initial mesangial development. Furthermore, the findings suggest that in pathogenic states accompanied by increased expression of PDGF [14.Betsholtz C. Raines E.W. Platelet-derived growth factor: A key regulator of connective tissue cells in embryogenesis and pathogenesis.Kidney Int. 1997; 51: 1361-1369Abstract Full Text PDF PubMed Scopus (82) Google Scholar], mesangial cell proliferation and migration may also be associated with synthesis and adherence to laminin-8/9. Further investigations of these specific cell-matrix behaviors may lead to effective therapies that treat mesangial disease.