Trends in Genetics
ReviewUsing Genetic and Species Diversity to Tackle Kidney Disease
Section snippets
The Need for Animal Models to Study Kidney Disease
The past two decades have seen a tremendous gain in tools and approaches to study the genetic basis of kidney disease in humans. Genetics studies have moved from investigating genetic variation in single genes (i.e., candidate gene approach) using small populations (50–500 subjects) to large-scale genetic studies [genome-wide association study (GWAS); see Glossary] involving the assay of millions of SNPs by microarray, exome sequencing, and even whole-genome sequencing in populations of several
The Mouse as a Model for Kidney Disease
The mouse has been an important model in biomedical research for more than a century. The most widely studied inbred strain is C57BL/6 (B6), developed in 1918 by Clarence Cook Little, which has been used almost exclusively in kidney research. This is mainly because: the strain breeds well and is easy to maintain; there is a vast knowledge on this strain because it has been used by many investigators in the past 100 years; it is one of the few strains that allows for genetic manipulation using
The Rat as a Model for Kidney Disease
Several inbred rat genetic models exhibiting a robust kidney disease phenotype, including the development of overt proteinuria, decline in renal function, and significant histological damage (glomerulosclerosis, tubulointerstial injury/fibrosis, and vascular hypertrophy), are available [15]. For example, there are several hypertensive models, such as the stroke-prone spontaneously hypertensive rat (SHRSP) [16], Dahl salt-sensitive (DSS) [17,18], Fawn-hooded hypertensive rat (FHH) [19,20], and
Using Genetic Diversity in Rodents to Identify Candidate Genes
Both mice and rats are excellent models to study a complex genetic trait, such as kidney disease, and identify the underlying genetic factors. Given that environmental factors, such as diet and the microbiome, can be controlled, the number of individuals needed to have the same power of detection is smaller compared with humans. Over the past few decades, several genetic studies using crosses between inbred strains have been performed in mice and rats, and we have reviewed these previously [30
The Advantages of the Zebrafish
In addition to the common rodent models, there are several other animal models that are useful to study kidney disease. The zebrafish embryonic kidney (pronephros) shows histological and functional similarities to the mammalian adult nephron. This, combined with rapid ex utero development, transparent embryos, high fecundity, a well-characterized genome, and tools for gene editing, has led to an exponential growth in the number of zebrafish models to study kidney disease. Several excellent
Drosophila as an Emerging Model
Drosophila has a highly specialized filtration structure called the nephrocyte diaphragm, which shares similarities to the slit diaphragm structure of the mammalian glomerular podocyte [59]. Zhe Han developed Drosophila as a model to study podocyte biology and for large-scale genetic screens to identify and study novel genes that are involved in podocyte function and renal diseases. Similar to the experiment with Shroom3 in zebrafish, rescue of renal phenotypes in Drosophila with alleles from
Unconventional Animal Models
There have been some studies that suggest felids, including tigers, leopards, lions, cheetahs, and cougars, could provide interesting insights into the pathophysiology of CKD. For example, a study of 38 deceased captive wild felids originating from eight German zoological gardens found that 33 animals or 87% demonstrated significant renal lesions [62]. In >50% of these animals, significant tubular changes, including tubular epithelial degeneration, necrosis, and proteinaceous casts, were
Concluding Remarks and Future Perspectives
Despite the tremendous advances in human genetic studies, there is still a great need for animal models to study and better understand kidney disease and the genetic factors that are involved. The almost exclusive use of a few species (mouse and rat) with restricted genetic backgrounds (e.g., mostly C57BL/6 mice) has limited these studies and contributed to the reputation that animal models are limited and do not reflect the human condition. Exploring the large genetic variation in rodent
Acknowledgments
This work was supported by grants from the National Institutes of Health (R01 HL137673 to M.R.G. and P30 AG038070, U54 OD020351, and RO1 ES029916 to R.K.).
Glossary
- Albuminuria/proteinuria
- presence of albumin or protein in the urine, which is an indicator of renal damage.
- Blood urea nitrogen (BUN)
- elevated BUN is indicative of reduced renal function.
- CRE recombinase
- enzyme that catalyzes the site-specific recombination of DNA between loxP sites (see ‘Floxed genes’)
- CRISPR/Cas9
- a genome-editing system based on the ability of the Cas9 enzyme to cut DNA at a specific sequence as directed by a guide RNA sequence.
- Estimated glomerular filtration rate (eGFR)
- used in
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2024, Ecotoxicology and Environmental SafetyZebrafish as a powerful alternative model organism for preclinical investigation of nanomedicines
2022, Drug Discovery TodayCitation Excerpt :In this regard, zebrafish have received much attention for preclinical evaluation of nanomedicines because of their ability to screen these formulations quickly under in vivo conditions in an economical manner thus reducing disparities between in vitro and in vivo rodent studies. Several crucial attributes of zebrafish such as high fecundity (up to hundreds of eggs per day), low husbandry costs (as compared with rodents), well-characterized developmental stages, small size of embryos and larvae (0.5–5.0 mm depending on the stage of development), high level of genetic homology to humans (∼70%), rapid ex utero development, availability of transgenic lines and, most strikingly, optical transparency make this a promising model for preclinical investigation of nanomedicines (Fig. 1).12–15 The optical transparency of zebrafish larvae can be lengthened to several days either chemically (viz. by using 1-phenyl-2-thiourea) to suppress melanogenesis16 or using genetic manipulation (such as casper/crystal mutant).17
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