The Molecular Basis of Goodpasture and Alport Syndromes

Hudson, Billy G.

doi:10.1097/01.asn.0000141462.00630.76

Cited by 167 publications

(126 citation statements)

References 109 publications

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“…This developmental switch in gene expression is absolutely critical for the maturation of the GBM as a specialized plasma filtration barrier in the kidney. While most identified mutations in the genes encoding either α1(IV) or α2(IV) are embryonic lethal, most mutations in genes encoding the α3(IV), α4(IV), or α5(IV) chains leads to renal failure and deafness in adult patients with Alport's syndrome (Hudson, 2004;Hudson et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Mammalian collagen IV

Khoshnoodi

Pedchenko

Hudson

2008

Microscopy Res & Technique

569

487

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Four decades have passed since the first discovery of collagen IV by Kefalides in 1966. Since then collagen IV has been investigated extensively by a large number of research laboratories around the world. Advances in molecular genetics have resulted in identification of six evolutionary related mammalian genes encoding six different polypeptide chains of collagen IV. The genes are differentially expressed during the embryonic development, providing different tissues with specific collagen IV networks each having unique biochemical properties. Newly translated α-chains interact and assemble in the endoplasmic reticulum in a chain-specific fashion and form unique heterotrimers. Unlike most collagens, type IV collagen is an exclusive member of the basement membranes and through a complex inter-and intramolecular interactions form supramolecular networks that influence cell adhesion, migration, and differentiation. Collagen IV is directly involved in a number of genetic and acquired disease such as Alport's and Goodpasture's syndromes. Recent discoveries have also highlighted a new and direct role for collagen IV in the development of rare genetic diseases such as cerebral hemorrhage and porencephaly in infants and hemorrhagic stroke in adults. Years of intensive investigations have resulted in a vast body of information about the structure, function, and biology of collagen IV. In this review article, we will summarize essential findings on the structural and functional relationships of different collagen IV chains and their roles in health and disease.

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Section: Introductionmentioning

confidence: 99%

Mammalian collagen IV

Khoshnoodi

Pedchenko

Hudson

2008

Microscopy Res & Technique

569

487

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“…8 -10 Six genetically distinct collagen type IV ␣ chains form three different triple helical heterotrimers (protomers) in separate compartments of the mature glomerulus. 11,12 A network of collagen ␣1␣2␣1(IV) is found in the mesangial matrix, collagen ␣3␣4␣5(IV) is present in the GBM, and Bowman's capsule contains networks of both ␣1␣2␣1(IV) and ␣5␣6␣5(IV). 3,13 The immature GBMs of comma, S-shaped, and early capillary loop stage glomeruli all contain collagen ␣1␣2␣1(IV).…”

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confidence: 99%

“…Collagen networks then assemble through head to head interactions between NC1 domains of two protomers, to produce a NC1 hexamer structure. 11,12 Similarly, the amino termini of four protomers associate in an anti-parallel fashion, to form a three-dimensional network of polymerized collagen IV. 11,12 Mutations of the human COL4A3, COL4A4, and/or COL4A5 genes prevent the proper assembly of a stable ␣3␣4␣5(IV) network, resulting in Alport disease.…”

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confidence: 99%

“…11,12 Similarly, the amino termini of four protomers associate in an anti-parallel fashion, to form a three-dimensional network of polymerized collagen IV. 11,12 Mutations of the human COL4A3, COL4A4, and/or COL4A5 genes prevent the proper assembly of a stable ␣3␣4␣5(IV) network, resulting in Alport disease. 11,12,15,16 This disorder is characterized in kidney by an absence of collagen ␣3␣4␣5(IV) and persistence of collagen ␣1␣2␣1(IV) in the GBM, thickening and multilamination of the GBM, proteinuria, and in most cases eventually, renal failure.…”

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confidence: 99%

“…11,12 Mutations of the human COL4A3, COL4A4, and/or COL4A5 genes prevent the proper assembly of a stable ␣3␣4␣5(IV) network, resulting in Alport disease. 11,12,15,16 This disorder is characterized in kidney by an absence of collagen ␣3␣4␣5(IV) and persistence of collagen ␣1␣2␣1(IV) in the GBM, thickening and multilamination of the GBM, proteinuria, and in most cases eventually, renal failure. Mice homozygous for a Col4a3 mutation possess a strikingly similar phenotype, and therefore, represent an attractive experimental model of human Alport disease.…”

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confidence: 99%

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Cellular Origins of Type IV Collagen Networks in Developing Glomeruli

Abrahamson

Hudson²,

Stroganova³

et al. 2009

Journal of the American Society of Nephrology

183

148

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Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen ␣1␣2␣1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen ␣3␣4␣5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen ␣3␣4␣5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen ␣5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen ␣3␣4␣5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type. Basement membranes are thin sheets of extracellular matrix that underlie epithelial cells, including the vascular endothelium, and surround all muscle cells, Schwann cells, and adipocytes. They are composed of polymers of laminin and type IV collagen, and also contain nidogen/entactin, and proteoglycans. During glomerulogenesis, a basement membrane beneath developing endothelial cells fuses with a separate basement membrane layer beneath differentiating podocytes, to produce the glomerular basement membrane (GBM) shared on opposing surfaces by both cell types. 1 Unlike most basement membranes in the body, the laminin and collagen IV composition of the GBM changes temporally as the glomerulus develops. 2 The earliest GBMs of comma-and S-shaped nephrons contain laminin ␣1␤1␥1 (laminin 111), whereas those at later developmental stages and in adulthood contain laminin ␣5␤2␥1 (laminin 521). 2,3 Previously, we showed by postfixation immunoelectron microscopy that both endothelial cells and podocytes synthesize laminin ␣1 and ␤1 initially, and both cells then undergo a laminin isoform switch and synthesize laminin ␣5 and ␤2 as glomeruli mature. 4 The mechanism and reason why laminin replacement occurs are unknown, but

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Podocentric view of glomerular proteinuria: Focused on cytoskeletal changes and toward promising targeted therapies and challenges

Kuo

Liang

Chang

2021

The Kaohsiung J of Med Scie

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Among renal cells, podocytes (glomerular epithelial cells) are the most critical to prevent plasma proteins from excessive loss by forming their sophisticated foot processes (FP) and slit diaphragms (SD). A general finding in the glomeruli of patients with nephrotic syndrome is the foot processes "effacement" resulted from dysregulated actin cytoskeleton reorganization. Ultrastructural analysis in patients with nephrotic syndrome has demonstrated that such changes tend to be dynamic and can sometimes be reversible. In a more molecular sense, injured podocytes can no longer maintain their tight regulation and "retract" their FP, but not "efface" them.Past studies have revealed multiple exquisite mechanisms and arrays of proteins participating in the regulation of cytoskeletal rearrangement, and these mechanisms serve as potential targets to treat. A major challenge to develop specific therapies is the targeted mechanism has to be crucial and specific enough for podocyte-oriented kidney diseases, and it would be even better to manifest in most of the glomerulonephritis. Studies have shown many approaches targeting different mechanisms, but none of them has been proved to be effective in clinical medicine. Up to the present, Abatacept (Orencia) is the first (and the only) clinical targeted therapy demonstrating limited success. It inhibits the co-stimulatory response of B7-1 (CD80) induced in various types of glomerulonephritis. Future clinical studies have to be expanded to substantiate this highly specific targeted therapy because the Abatacept effect is not generally accepted even within the nephrology community. Nevertheless, there are ongoing searches for specific treatment targeting podocytes through various approaches.

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The Molecular Basis of Goodpasture and Alport Syndromes

Cited by 167 publications

References 109 publications

Mammalian collagen IV

Mammalian collagen IV

Cellular Origins of Type IV Collagen Networks in Developing Glomeruli

Podocentric view of glomerular proteinuria: Focused on cytoskeletal changes and toward promising targeted therapies and challenges

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