Clin Exp Nephrol DOI 10.1007/s10157-014-1025-7
COMMENTARY
Glomerular basement membrane (GBM) abnormalities are worth pursuing Junko Takagi • Hiroyuki Morita • Koji Kimata
Received: 18 July 2014 / Accepted: 21 August 2014 Ó Japanese Society of Nephrology 2014
Historically, the glomerular basement membrane (GBM) has drawn the attention of nephrologists for more than three decades because the amassed evidence clearly indicated that it functioned as the filtration barrier that keeps albumin in the circulation [1, 2]. A paradigm shift occurred in 1998, when a slit membrane protein, nephrin, was identified as the responsible gene in patients with congenital nephrotic syndrome [3]. After the discovery of nephrin, the prevailing view was that slit membranes located in the adjoining foot processes of podocytes contain a pore responsible for preventing the passage of plasma proteins [2]. Proteinuria, however, is a very prevalent phenomenon observed in a variety of abnormalities. Subsequent evidence showed that abnormalities in the GBM could also lead to massive proteinuria and kidney failure [4]. Thus, like the swinging of a pendulum [2], the GBM has re-captured the attention of nephrologists. There is another attractive aspect of the GBM. It is not a cellular component but an extracellular matrix (ECM). The ECM is fully capable of providing biochemical support to the surrounding cells and modulating cellular activities, which makes it far from being simply a structural support consisting of glycoproteins and sugars (polysaccharides) This comment refers to the article available at doi:10.1007/s10157014-1008-8. J. Takagi H. Morita (&) Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan e-mail: [email protected] K. Kimata Advanced Medical Research Center, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
[5]. Understanding the idea of ‘cell–matrix interaction as a regulator of cellular behavior’ [6–8] is important in understanding the theoretical background of why GBM abnormalities are subjects of study. Impressively, mutations of the genes encoding major GBM molecules lead to glomerular diseases. For example, collagen type IV is the most abundant glycoprotein of the GBM. Six different a-chains of type IV collagen are known. They include the a1(IV), a2(IV), a3(IV), a4(IV), a5(IV), and a6(IV) chains, which are encoded by the COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, and COL4A6 genes, respectively [9]. A mutation in any one of the COL4A3, COL4A4, or COL4A5 genes causes Alport syndrome [10]. In this issue of Clinical and Experimental Nephrology, Masuda and colleagues report on the GBM abnormalities observed in 50 patients with IgA nephropathy who underwent renal biopsy [11]. In their effort to elucidate the morphologic changes of the GBM, they immunostained a2(IV) and a5(IV) in the same 3 lm-thick frozen sections and found various alterations in the expression of these chains. Although immunostaining for the a2(IV) and a5(IV) chains was performed in previous studies dealing with acquired glomerulonephritis [12], membranous nephropathy [13], and IgA nephropathy [14, 15], none of them clearly showed reduced a5(IV) expression and definitely increased a2(IV) expression in the thickened GBM, as Masuda and colleagues have done. Importantly, this pattern of expression partially resembles that in X-linked and autosomal recessive Alport syndrome in which analyses of homo-trimeric and hetero-trimeric combinations of the alpha chains have been performed [16, 17]. In Alport syndrome, the normal collagen IV network in the GBM, which consists primarily of cross-linked a3, a4, a5(IV) protomers [9, 16], is completely lost, and a compensatory
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increase in the a1, a1, a2(IV) network takes place, which is abundantly expressed in the embryonic GBM but barely detectable in the adult GBM [9, 16]. Whether there is a compensatory increase in the a1, a1, a2(IV), and/or homotrimeric [a1(IV)3] networks in IgA nephropathy remains unknown. This issue should be examined in the future. It may be worth noting other limitations of this study. First, there are numerous variations in the clinical picture of IgA nephropathy. Unfortunately, there is not yet sufficient evidence to connect morphologic abnormalities appearing in the article by Masuda and colleagues with certain manifestation(s) in IgA nephropathy, such as the proteinuric state, the level of hematuria, and the rate of decline in the glomerular filtration rate. Clarifying this issue could allow us to use morphologic alterations as a tool to predict clinical courses in IgA nephropathy. Second, although the authors clearly demonstrated a decrease in mesangial a2(IV) expression in their double staining experiments, mechanisms leading to this change remain unknown. Third, it remains to be seen whether the morphologic alterations of the GBM are the causes or results of glomerular cell damage. Lastly, Masuda and colleagues have advanced our understanding of GBM abnormalities in IgA nephropathy. Their efforts to evaluate 3-dimensional ultrastructural changes of the GBM are appreciated because biochemical studies in the past decades have shown that molecular constituents of the ECM including the GBM specifically interact with one another, and we can now assume that any disturbance in the 3-dimensional molecular architectures of the GBM is associated with abnormal functions of glomerular cells. Their report will contribute to further draw our attention to abnormalities in the GBM that are associated with IgA nephropathy. Conflict of interest interests.
All authors have declared no competing
References 1. Kanwar YS. Biophysiology of glomerular filtration and proteinuria. Lab Invest. 1984;51(1):7–21.
123
2. Farquhar MG. The glomerular basement membrane: not gone, just forgotten. J Clin Invest. 2006;116(8):2090–3. 3. Tryggvason K. Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J Am Soc Nephrol. 1999;10(11):2440–5. 4. Jarad G, Cunningham J, Shaw AS, Miner JH. Proteinuria precedes podocyte abnormalities in Lamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier. J Clin Invest. 2006;116(8):2272–9. 5. Gao Y, Liu S, Huang J, Guo W, Chen J, et al. The ECM-cell interaction of cartilage extracellular matrix on chondrocytes. Biomed Res Int. 2014;2014:648459. doi:10.1155/2014/64845. 6. Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol. 2002;14(5):608–16. 7. Jun JI, Lau LF. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov. 2011;10(12):945–63. doi:10.1038/nrd3599. 8. Neill T, Schaefer L, Iozzo RV. Instructive roles of extracellular matrix on autophagy. Am J Pathol. 2014;. doi:10.1016/j.ajpath. 2014.05.010. 9. Zhou J, Reeders ST. The alpha chains of type IV collagen. Contrib Nephrol. 1996;117:80–104. 10. Kruegel J, Rubel D, Gross O. Alport syndrome–insights from basic and clinical research. Nat Rev Nephrol. 2013;9(3):170–8. doi:10.1038/nrneph.2012.259. 11. Masuda Y, Yamanaka N, Ishikawa A, Kataoka M, Arai T, et al. Glomerular basement membrane injuries in IgA nephropathy evaluated by double immunostaining for a5(IV) and a2(IV) chains of type IV collagen and low-vacuum scanning electron microscopy. Clin Exp Nephrol. 2014;. doi:10.1007/s10157-0141008-8. 12. Sanna-Cherchi S, Carnevali ML, Martorana D, Cravedi P, Maggiore U, et al. Alterations of type IV collagen alpha chains in patients with chronic acquired glomerulopathies: mRNA levels, protein expression and urinary loss. Am J Nephrol. 2007;27(2):129–37. 13. Kim Y, Butkowski R, Burke B, Kleppel MM, Crosson J, et al. Differential expression of basement membrane collagen in membranous nephropathy. Am J Pathol. 1991;139(6):1381–8. 14. Kamimura H, Honda K, Nitta K, Horita S, Kobayashi H, et al. Glomerular expression of alpha2(IV) and alpha5(IV) chains of type IV collagen in patients with IgA nephropathy. Nephron. 2002;91(1):43–50. 15. Horita S, Nitta K, Honda K, Kobayashi H, Uchida K, et al. A case of IgA nephropathy with split reduction of alpha5(V) chain of type IV collagen in glomerular basement membrane. Nephron. 1998;80(4):482–3. 16. Suh JH, Miner JH. The glomerular basement membrane as a barrier to albumin. Nat Rev Nephrol. 2013;9(8):470–7. doi:10. 1038/nrneph.2013.109. 17. Pihlajaniemi T. Molecular properties of the glomerular basement membrane. Contrib Nephrol. 1996;117:46–79.
COMMENTARY
Glomerular basement membrane (GBM) abnormalities are worth pursuing Junko Takagi • Hiroyuki Morita • Koji Kimata
Received: 18 July 2014 / Accepted: 21 August 2014 Ó Japanese Society of Nephrology 2014
Historically, the glomerular basement membrane (GBM) has drawn the attention of nephrologists for more than three decades because the amassed evidence clearly indicated that it functioned as the filtration barrier that keeps albumin in the circulation [1, 2]. A paradigm shift occurred in 1998, when a slit membrane protein, nephrin, was identified as the responsible gene in patients with congenital nephrotic syndrome [3]. After the discovery of nephrin, the prevailing view was that slit membranes located in the adjoining foot processes of podocytes contain a pore responsible for preventing the passage of plasma proteins [2]. Proteinuria, however, is a very prevalent phenomenon observed in a variety of abnormalities. Subsequent evidence showed that abnormalities in the GBM could also lead to massive proteinuria and kidney failure [4]. Thus, like the swinging of a pendulum [2], the GBM has re-captured the attention of nephrologists. There is another attractive aspect of the GBM. It is not a cellular component but an extracellular matrix (ECM). The ECM is fully capable of providing biochemical support to the surrounding cells and modulating cellular activities, which makes it far from being simply a structural support consisting of glycoproteins and sugars (polysaccharides) This comment refers to the article available at doi:10.1007/s10157014-1008-8. J. Takagi H. Morita (&) Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan e-mail: [email protected] K. Kimata Advanced Medical Research Center, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
[5]. Understanding the idea of ‘cell–matrix interaction as a regulator of cellular behavior’ [6–8] is important in understanding the theoretical background of why GBM abnormalities are subjects of study. Impressively, mutations of the genes encoding major GBM molecules lead to glomerular diseases. For example, collagen type IV is the most abundant glycoprotein of the GBM. Six different a-chains of type IV collagen are known. They include the a1(IV), a2(IV), a3(IV), a4(IV), a5(IV), and a6(IV) chains, which are encoded by the COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, and COL4A6 genes, respectively [9]. A mutation in any one of the COL4A3, COL4A4, or COL4A5 genes causes Alport syndrome [10]. In this issue of Clinical and Experimental Nephrology, Masuda and colleagues report on the GBM abnormalities observed in 50 patients with IgA nephropathy who underwent renal biopsy [11]. In their effort to elucidate the morphologic changes of the GBM, they immunostained a2(IV) and a5(IV) in the same 3 lm-thick frozen sections and found various alterations in the expression of these chains. Although immunostaining for the a2(IV) and a5(IV) chains was performed in previous studies dealing with acquired glomerulonephritis [12], membranous nephropathy [13], and IgA nephropathy [14, 15], none of them clearly showed reduced a5(IV) expression and definitely increased a2(IV) expression in the thickened GBM, as Masuda and colleagues have done. Importantly, this pattern of expression partially resembles that in X-linked and autosomal recessive Alport syndrome in which analyses of homo-trimeric and hetero-trimeric combinations of the alpha chains have been performed [16, 17]. In Alport syndrome, the normal collagen IV network in the GBM, which consists primarily of cross-linked a3, a4, a5(IV) protomers [9, 16], is completely lost, and a compensatory
123
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increase in the a1, a1, a2(IV) network takes place, which is abundantly expressed in the embryonic GBM but barely detectable in the adult GBM [9, 16]. Whether there is a compensatory increase in the a1, a1, a2(IV), and/or homotrimeric [a1(IV)3] networks in IgA nephropathy remains unknown. This issue should be examined in the future. It may be worth noting other limitations of this study. First, there are numerous variations in the clinical picture of IgA nephropathy. Unfortunately, there is not yet sufficient evidence to connect morphologic abnormalities appearing in the article by Masuda and colleagues with certain manifestation(s) in IgA nephropathy, such as the proteinuric state, the level of hematuria, and the rate of decline in the glomerular filtration rate. Clarifying this issue could allow us to use morphologic alterations as a tool to predict clinical courses in IgA nephropathy. Second, although the authors clearly demonstrated a decrease in mesangial a2(IV) expression in their double staining experiments, mechanisms leading to this change remain unknown. Third, it remains to be seen whether the morphologic alterations of the GBM are the causes or results of glomerular cell damage. Lastly, Masuda and colleagues have advanced our understanding of GBM abnormalities in IgA nephropathy. Their efforts to evaluate 3-dimensional ultrastructural changes of the GBM are appreciated because biochemical studies in the past decades have shown that molecular constituents of the ECM including the GBM specifically interact with one another, and we can now assume that any disturbance in the 3-dimensional molecular architectures of the GBM is associated with abnormal functions of glomerular cells. Their report will contribute to further draw our attention to abnormalities in the GBM that are associated with IgA nephropathy. Conflict of interest interests.
All authors have declared no competing
References 1. Kanwar YS. Biophysiology of glomerular filtration and proteinuria. Lab Invest. 1984;51(1):7–21.
123
2. Farquhar MG. The glomerular basement membrane: not gone, just forgotten. J Clin Invest. 2006;116(8):2090–3. 3. Tryggvason K. Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J Am Soc Nephrol. 1999;10(11):2440–5. 4. Jarad G, Cunningham J, Shaw AS, Miner JH. Proteinuria precedes podocyte abnormalities in Lamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier. J Clin Invest. 2006;116(8):2272–9. 5. Gao Y, Liu S, Huang J, Guo W, Chen J, et al. The ECM-cell interaction of cartilage extracellular matrix on chondrocytes. Biomed Res Int. 2014;2014:648459. doi:10.1155/2014/64845. 6. Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol. 2002;14(5):608–16. 7. Jun JI, Lau LF. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov. 2011;10(12):945–63. doi:10.1038/nrd3599. 8. Neill T, Schaefer L, Iozzo RV. Instructive roles of extracellular matrix on autophagy. Am J Pathol. 2014;. doi:10.1016/j.ajpath. 2014.05.010. 9. Zhou J, Reeders ST. The alpha chains of type IV collagen. Contrib Nephrol. 1996;117:80–104. 10. Kruegel J, Rubel D, Gross O. Alport syndrome–insights from basic and clinical research. Nat Rev Nephrol. 2013;9(3):170–8. doi:10.1038/nrneph.2012.259. 11. Masuda Y, Yamanaka N, Ishikawa A, Kataoka M, Arai T, et al. Glomerular basement membrane injuries in IgA nephropathy evaluated by double immunostaining for a5(IV) and a2(IV) chains of type IV collagen and low-vacuum scanning electron microscopy. Clin Exp Nephrol. 2014;. doi:10.1007/s10157-0141008-8. 12. Sanna-Cherchi S, Carnevali ML, Martorana D, Cravedi P, Maggiore U, et al. Alterations of type IV collagen alpha chains in patients with chronic acquired glomerulopathies: mRNA levels, protein expression and urinary loss. Am J Nephrol. 2007;27(2):129–37. 13. Kim Y, Butkowski R, Burke B, Kleppel MM, Crosson J, et al. Differential expression of basement membrane collagen in membranous nephropathy. Am J Pathol. 1991;139(6):1381–8. 14. Kamimura H, Honda K, Nitta K, Horita S, Kobayashi H, et al. Glomerular expression of alpha2(IV) and alpha5(IV) chains of type IV collagen in patients with IgA nephropathy. Nephron. 2002;91(1):43–50. 15. Horita S, Nitta K, Honda K, Kobayashi H, Uchida K, et al. A case of IgA nephropathy with split reduction of alpha5(V) chain of type IV collagen in glomerular basement membrane. Nephron. 1998;80(4):482–3. 16. Suh JH, Miner JH. The glomerular basement membrane as a barrier to albumin. Nat Rev Nephrol. 2013;9(8):470–7. doi:10. 1038/nrneph.2013.109. 17. Pihlajaniemi T. Molecular properties of the glomerular basement membrane. Contrib Nephrol. 1996;117:46–79.
