Progressive Kidney Damage That Marks Alport Traced in Dogs, Giving Research New Model
Kidney complications in Alport syndrome start with mesangial cells invading small blood vessels in those organs, a study conducted in a dog model of the disease showed. This confirmed a process already seen in mice, only now in a larger and more representative mammal.
Because of the similarities observed in disease progression — and also seen in patients — these findings suggest that the dog is a suitable large animal model for studies of both changes in Alport syndrome and for preclinical tests of potential therapeutics.
The study, “X-Linked Alport Dogs Demonstrate Mesangial Filopodial Invasion of the Capillary Tuft as an Early Event in Glomerular Damage” was published in the scientific journal PLOS One.
Researchers led by Dr. Dominic Cosgrove of the Center for Basic Research, Boys Town National Research Hospital in Omaha, Nebraska, monitored dogs with X-linked Alport syndrome and their wild type littermates through clinical data and kidney biopsy results.
Kidney biopsies were performed at pre-defined milestones, such as onset of microalbuminuria (or a moderate increase in the urine of albumin, an early sign of kidney disease), obvious proteinuria (or protein in urine-again a sign of kidney dysfunction), the onset of azotemia (or abnormally high levels of nitrogen containing compounds in the blood-a sign of insufficient filtering of blood by the kidneys), and, finally, at euthanasia. Biopsy samples were then analyzed for the proteins they expressed, including at very high resolution using an electron microscope.
The results showed that kidney function progressively decreased in dogs with X-linked Alport syndrome, while the fibrosis between tissues increased together with the hardening of the kidneys.
At the initial biopsy, when microalbuminuria levels were first recorded, the only structural abnormality observed was a mild segmental multilamination of the kidneys’ basement membrane (an extracellular support layer, further explained below). This was more pronounced in the second biopsy, when proteinuria developed. At that time, two proteins — called mesangial laminin 211 and integrin α8β1 — started to accumulate in the basement membrane. This coincided with the kidneys’ small blood vessels being invaded by projections of mesangial cells, specialized cells that help blood flow in the kidneys.
Alport syndrome is a genetic condition caused by mutations in genes encoding for type IV collagen. The X-linked version of the disease is the most common and accounts for around 80% of all human Alport syndrome cases. The disease is well-characterized in humans, mice, and dogs, with all of them having similar clinical manifestations that ultimately lead to end-stage kidney disease.
The basement membrane of the kidneys plays a crucial role in the filtration of blood. Around half of the basement membrane is composed of a type IV collagen, which is important in maintaining both stability and function.