Creation of X-linked Alport Syndrome Rat Model with Col4a5 Deficiency

Alport syndrome is an inherited chronic human kidney disease, characterized by glomerular basement membrane abnormalities. This disease is caused by mutations in COL4A3, COL4A4, or COL4A5 gene. The knockout mice for Col4α3, Col4α4, and Col4α5 are developed and well characterized for the study of Alport syndrome. However, disease progression and effects of pharmacological therapy depend on the genetic variability. This model is reliable only to mice. Therefore in this study, we created a novel Alport syndrome rat model utilizing rGONAD technology. Col4α5 deficient rats showed hematuria, proteinuria, high levels of BUN, Cre, and then died at 18 to 28 weeks of age (Hemizygous mutant males). Histological and ultrastructural analyses displayed the abnormalities including parietal cell hyperplasia, mesangial sclerosis, and interstitial fibrosis. Then, we demonstrated that α3/α4/α5 (IV) and α5/α5/α6 (IV) chains of type IV collagen disrupted in the Col4α5 deficient rats. Moreover, immunofluorescence analyses revealed that some glomeruli of Col4α5 mutant rats were found to be disrupted from postnatal day 0. Thus, Col4α5 mutant rat is a reliable candidate for Alport syndrome model for underlying the mechanism of renal diseases and further identifying potential therapeutic targets for human renal diseases.

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Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

Scientific Reports ◽

10.1038/s41598-021-00354-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Masumi Namba ◽

Tomoe Kobayashi ◽

Mayumi Kohno ◽

Takayuki Koyano ◽

Takuo Hirose ◽

...

Keyword(s):

Rat Model ◽

Alport Syndrome ◽

Interstitial Fibrosis ◽

Kidney Diseases ◽

Human Kidney ◽

Pharmacological Therapy ◽

Renal Diseases ◽

Cell Hyperplasia ◽

Type Iv ◽

Mutant Rat

AbstractAlport syndrome is an inherited chronic human kidney disease, characterized by glomerular basement membrane abnormalities. This disease is caused by mutations in COL4A3, COL4A4, or COL4A5 gene. The knockout mice for Col4α3, Col4α4, and Col4α5 are developed and well characterized for the study of Alport syndrome. However, disease progression and effects of pharmacological therapy depend on the genetic variability. This model was reliable only to mouse. In this study, we created a novel Alport syndrome rat model utilizing the rGONAD technology, which generated rat with a deletion of the Col4α5 gene. Col4α5 deficient rats showed hematuria, proteinuria, high levels of BUN, Cre, and then died at 18 to 28 weeks of age (Hemizygous mutant males). Histological and ultrastructural analyses displayed the abnormalities including parietal cell hyperplasia, mesangial sclerosis, and interstitial fibrosis. Then, we demonstrated that α3/α4/α5 (IV) and α5/α5/α6 (IV) chains of type IV collagen disrupted in Col4α5 deficient rats. Thus, Col4α5 mutant rat is a reliable candidate for the Alport syndrome model for underlying the mechanism of kidney diseases and further identifying potential therapeutic targets for human renal diseases.

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The pathogenesis of Alport syndrome involves type IV collagen molecules containing the α3(IV) chain: Evidence from anti-GBM nephritis after renal transplantation

Kidney International ◽

10.1038/ki.1992.276 ◽

1992 ◽

Vol 42 (1) ◽

pp. 179-187 ◽

Cited By ~ 61

Author(s):

Billy G. Hudson ◽

Raghuram Kalluri ◽

Sripad Gunwar ◽

Manfred Weber ◽

Fernando Ballester ◽

...

Keyword(s):

Renal Transplantation ◽

Alport Syndrome ◽

Type Iv Collagen ◽

Type Iv ◽

Collagen Molecules

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Quantitative analysis of type IV collagen subchains in the glomerular basement membrane of patients with Alport syndrome with confocal microscopy

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfl090 ◽

2006 ◽

Vol 21 (7) ◽

pp. 1838-1847 ◽

Cited By ~ 3

Author(s):

Jian Su ◽

Zhi-Hong Liu ◽

Cai-Hong Zeng ◽

Wei-Gong ◽

Hui-Ping Chen ◽

...

Keyword(s):

Quantitative Analysis ◽

Confocal Microscopy ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Alport Syndrome ◽

Type Iv Collagen ◽

Type Iv

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Distribution of Type IV Collagen in the Cochlea in Alport Syndrome

Archives of Otolaryngology - Head and Neck Surgery ◽

10.1001/archotol.131.11.1007 ◽

2005 ◽

Vol 131 (11) ◽

pp. 1007 ◽

Cited By ~ 38

Author(s):

Andreas F. Zehnder ◽

Joe C. Adams ◽

Peter A. Santi ◽

Arthur G. Kristiansen ◽

Chitsuda Wacharasindhu ◽

...

Keyword(s):

Alport Syndrome ◽

Type Iv Collagen ◽

Type Iv

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Renal disease in elderly patients

Reviews in Clinical Gerontology ◽

10.1017/s0959259897007430 ◽

1997 ◽

Vol 7 (4) ◽

pp. 299-307 ◽

Cited By ~ 6

Author(s):

Jerome G Porush ◽

Pierre F Faubert

Keyword(s):

Type Iv Collagen ◽

Gradual Increase ◽

Interstitial Fibrosis ◽

Basement Membranes ◽

The Body ◽

Glomerular Sclerosis ◽

Physiological Changes ◽

Kidney Weight ◽

Type Iv ◽

Glomerular Size

Like other organs in the body, the kidneys undergo age-associated anatomical, structural and physiological changes. Starting at 50 years of age, there is a 3-10% decline in kidney weight for each subsequent decade of life, with the loss of cortical mass greater than medullary mass. In fact, the number of glomeruli start to decrease progressively after age 40, and the number of sclerotic glomeruli increases, making the distinction between involutional and disease-related sclerosis unclear in some cases. The outer cortical glomeruli are, in general, more extensively involved than deeper glomeruli, but glomerular size does not change. In general, the loss of the glomerular mass is proportional to the loss of tubular mass, maintaining glomerulotubular balance. In addition to glomerular sclerosis, there is a gradual increase in interstitial fibrosis, and there is focal thickening of both glomerular and tubular basement membranes, probably due to the accumulation of type IV collagen.

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