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 Col4 alpha 3, Col4 alpha 4, and Col4 alpha 5 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 Col4 alpha 5 gene. Col4 alpha 5 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 alpha 3/alpha 4/alpha 5 (IV) and alpha 5/alpha 5/alpha 6 (IV) chains of type IV collagen disrupted in Col4 alpha 5 deficient rats. Thus, Col4 alpha 5 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.

Automated summary

Alport syndrome is a genetic chronic kidney disease characterized by abnormalities in glomerular basement membrane. A novel rat model with Col4 alpha 5 deficiency was created to study this disease, showing characteristic symptoms and disruptions in collagen chains, providing a reliable candidate for investigating kidney disease mechanisms and potential therapeutic targets.