Role of distinct type IV collagen networks in glomerular development and function

Harvey, Scott J.; Zheng, Keqin; Sado, Yoshikazu; Naito, Ichiro; Ninomiya, Yoshifumi; Jacobs, Robert M.; Hudson, Billy G.; Thorner, Paul

doi:10.1046/j.1523-1755.1998.00188.x

Cited by 102 publications

(111 citation statements)

References 24 publications

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“…28 -31 The presence of cysteine-rich ␣3(IV) and ␣4(IV) chains, forming with ␣5(IV) a network containing loops and supercoiled triple helices stabilized by disulfide bonds between the chains, seems to be important with regards to the longterm stability of the GBM and its role as a filter. 26,32 Despite the increasing number of AS mutations reported in the literature [12][13][14][15][16][17][18][19] and the existence of AS animal models, [33][34][35][36][37] several questions regarding the consequences of AS mutations on the collagen organization within the GBM and the mechanisms responsible for the progressive development of AS nephropathy remain unanswered. A striking feature observed in the majority of AS is the absence of all three ␣3(IV), ␣4(IV), and ␣5(IV) chains within the GBM although only one of these chains is actually mutated.…”

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confidence: 99%

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Heidet

Cai

Guicharnaud

et al. 2000

The American Journal of Pathology

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Alport syndrome is an inherited nephropathy characterized by alterations of the glomerular basement membrane because of mutations in type IV collagen genes. COL4A5 mutations, causing X-linked Alport syndrome, frequently result in the loss of the ␣5 chains of type IV collagen in basement membranes. This is associated with the absence of the ␣3(IV) and ␣4(IV) chains and increased amounts of ␣1(IV) and ␣2(IV) in glomerular basement membranes. The mechanisms resulting in such a configuration are still controversial and are of fundamental importance for understanding the pathology of the disease and for considering gene therapy. In this article we studied, for the first time, type IV collagen expression in kidneys from X-linked Alport syndrome patients, using in situ hybridization and immunohistochemistry. We show that, independent of the type of mutation and of the level of COL4A5 transcription, both COL4A3 and COL4A4 genes are actively transcribed in podocytes. Moreover, using immunofluorescence amplification, we were able to demonstrate that the ␣3 chain of type IV collagen was present in the podocytes of all patients. Finally, the ␣1(IV) chain, which accumulates within glomerular basement membranes, was found to be synthesized by mesangial/endothelial cells. These results strongly suggest that, contrary to what has been found in dogs affected with X-linked Alport syndrome, there is no transcriptional co-regulation of COL4A3, COL4A4, and COL4A5 genes in humans, and that the absence of ␣3(IV) to ␣5(IV) in glomerular basement membranes in the patients results from events downstream of transcription, RNA processing, and protein synthesis.

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confidence: 99%

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Heidet

Cai

Guicharnaud

et al. 2000

The American Journal of Pathology

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“…Similarly, actin was not detectable in normal or affected dog ears at 11 days of age, but was present by the time dogs had acquired high-tone hearing. The situation for the affected dog ear is then comparable to the GBM in these animals, 33 namely ␣3/␣4/␣5 network is not necessary for the development of normal structure and function, but may play a critical role instead in the long-term maintenance of function.…”

Section: Discussionmentioning

confidence: 99%

“…46 The renal disease in Alport syndrome can be viewed as a failure of this developmental switch, 16 an event that has been demonstrated in the Samoyed model. 33 It was also established through this model that only the ␣1/␣2 network was essential for normal glomerular development, whereas the ␣3/␣4/␣5 network was essential for longterm stability of the GBM and maintenance of glomerular function. In other words, GBM deterioration in Alport syndrome was a postnatal process.…”

Section: Discussionmentioning

confidence: 99%

“…29 The latter model results from a nonsense mutation in the COL4A5 gene 30 and closely mimics human X-linked Alport syndrome. [31][32][33] Studies on the COL4A3 knockout mouse suggested changes in the stria vascularis as the possible cause of hearing loss in Alport syndrome, whereas previous studies in the dog model suggested the basilar membrane might be involved. The canine studies were performed before antibodies specific for all six ␣-chains were available.…”

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confidence: 99%

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The Inner Ear of Dogs with X-Linked Nephritis Provides Clues to the Pathogenesis of Hearing Loss in X-Linked Alport Syndrome

Harvey

Mount

Sado

et al. 2001

The American Journal of Pathology

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Alport syndrome is an inherited disorder of type IV collagen with progressive nephropathy, ocular abnormalities, and high-tone sensorineural deafness. In X-linked Alport syndrome, mutations in the COL4A5 gene encoding the ␣5 chain of type IV collagen lead to loss of the ␣3/␣4/␣5 network and increased susceptibility of the glomerular basement membrane to long-term damage. The molecular defects that underlie the otopathology in this disease remain poorly understood. We used a canine model of X-linked Alport syndrome to determine the expression of type IV collagen ␣-chains in the inner ear. By 1 month in normal adult dogs, the ␣3, ␣4, and ␣5 chains were co-expressed in a thin continuous line extending along the basilar membrane and the internal and external sulci, with the strongest expression along the lateral aspect of the spiral ligament in the basal turn of the cochlea. Affected dogs showed complete absence of the ␣3/␣4/␣5 network. The lateral aspect of the spiral ligament is populated by tension fibroblasts that express ␣-smooth muscle actin and nonmuscle myosin and are postulated to generate radial tension on the basilar membrane via the extracellular matrix for reception of high frequency sound. We propose that in Alport syndrome, the loss of the ␣3/␣4/␣5 network eventually weakens the interaction of these cells with their extracellular matrix, resulting in reduced tension on the basilar membrane and the inability to respond to high frequency sounds.

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“…PAMS staining detects argyrophilic molecules including collagenous reticular fibers, thin structural elements that provide supporting framework to many organs, and components of basement membranes. When analyzing nephron morphology, use of silver stains clearly defines the glomerular, and basement membranes and mesangium (Herrera and Lott, 1996;Harvey et al, 1998;Adler et al, 2000). However, although these stains have been used extensively in a variety of animals, the molecular specificity of these stains has not been investigated in crocodilians.…”

Section: Methodsmentioning

confidence: 99%

Morphology and Histochemistry of Juvenile American Alligator (Alligator mississippiensis) Nephrons

Moore

Hyndman

Cox

et al. 2009

The Anatomical Record

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Here we present a detailed morphological description of the alligator (Alligator mississippiensis) kidney and nephron. We present a series of histological, histochemical, and immunohistochemical markers that clearly define the seven regions of the alligator nephron. The alligator kidney is composed of many paired (mirrored) lobules on each kidney (lobe). Single nephrons span the width of lobules three times. The fine structure of glomeruli, lying in rows spanning the height of the lobule, is resolved by periodic acid methionine silver (PAMS) and periodic acid Schiff 's (PAS) histochemistry. Glomeruli are connected to the proximal tubule (PT) via a neck segment. The PT is alcian blue-negative, making it distinct from the distal tubule (DT), connecting segment (CS), and collecting duct (CD). The PT is clearly identifiable by a PAS-positive brush border membrane. The PT is connected to the DT via an intermediate segment (IS) that makes a 180 turn to connect these tubules. PAMS-positive material is found in the lumens of the PT, IS, and DT. Also, PAMS-positive granules are found in the DT, CS, and CD. Immunolocalization of the Na þ , K þ -ATPase to the basolateral membrane of the DT, CS, and CD suggests a role of this enzyme in driving primary and secondary transport processes in these segments, including bicarbonate transport into the lumen of the DT (leading to an alkaline urine). Through the techniques described here, we have identified a series of distinct markers to be used by pathologists, veterinarians, and researchers to easily identify alligator nephron segments. Anat Rec, 292:1670Rec, 292: -1676Rec, 292: , 2009. V V C 2009 Wiley-Liss, Inc.Key words: Alligator mississippiensis; kidney; nephron; histochemistry; Na þ , K þ -ATPaseThe kidneys' primary functions, the excretion of nitrogenous wastes and the maintenance of water and ion balance, are achieved through three fundamental mechanisms: glomerular filtration, tubular reabsorption, and secretion. To understand these physiological processes, a description of the morphological structures and kidney cell types is integral. Kidneys from various vertebrate species have been well investigated (Dantzler, 1980;Dantzler and Braun, 1980;Schmidt-Nielsen, 1988;Braun, 1998); whereas, knowledge of the crocodilian kidney is more limited. Previous studies of alligator nephrons have investigated general morphology (Huber, 1917), general nephron composition (Ventura et al.,

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Role of distinct type IV collagen networks in glomerular development and function

Cited by 102 publications

References 24 publications

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

The Inner Ear of Dogs with X-Linked Nephritis Provides Clues to the Pathogenesis of Hearing Loss in X-Linked Alport Syndrome

Morphology and Histochemistry of Juvenile American Alligator (Alligator mississippiensis) Nephrons

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