Experimental Models of Polycystic Kidney Disease: Applications and Therapeutic Testing

Polycystic kidney diseases (PKDs) are genetic disorders characterized by the formation and expansion of numerous fluid-filled renal cysts, damaging normal parenchyma and often leading to kidney failure. Although PKDs comprise a broad range of different diseases, with substantial genetic and phenotypic heterogeneity, an association with primary cilia represents a common theme. Great strides have been made in the identification of causative genes, furthering our understanding of the genetic complexity and disease mechanisms, but only one therapy so far has shown success in clinical trials and advanced to US Food and Drug Administration approval. A key step in understanding disease pathogenesis and testing potential therapeutics is developing orthologous experimental models that accurately recapitulate the human phenotype. This has been particularly important for PKDs because cellular models have been of limited value; however, the advent of organoid usage has expanded capabilities in this area but does not negate the need for whole-organism models where renal function can be assessed. Animal model generation is further complicated in the most common disease type, autosomal dominant PKD, by homozygous lethality and a very limited cystic phenotype in heterozygotes while for autosomal recessive PKD, mouse models have a delayed and modest kidney disease, in contrast to humans. However, for autosomal dominant PKD, the use of conditional/inducible and dosage models have resulted in some of the best disease models in nephrology. These have been used to help understand pathogenesis, to facilitate genetic interaction studies, and to perform preclinical testing. Whereas for autosomal recessive PKD, using alternative species and digenic models has partially overcome these deficiencies. Here, we review the experimental models that are currently available and most valuable for therapeutic testing in PKD, their applications, success in preclinical trials, advantages and limitations, and where further improvements are needed.