Modeling congenital kidney diseases in Xenopus laevis

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in ∼1/500 live births and are a leading cause of pediatric kidney failure. With an average wait time of 3-5 years for a kidney transplant, the need is high for the development of new strategies aimed at reducing the incidence of CAKUT and preserving renal function. Next-generation sequencing has uncovered a significant number of putative causal genes, but a simple and efficient model system to examine the function of CAKUT genes is needed. Xenopus laevis (frog) embryos are well-suited to model congenital kidney diseases and to explore the mechanisms that cause these developmental defects. Xenopus has many advantages for studying the kidney: the embryos develop externally and are easily manipulated with microinjections, they have a functional kidney in ∼2 days, and 79% of identified human disease genes have a verified ortholog in Xenopus This facilitates high-throughput screening of candidate CAKUT-causing genes. In this Review, we present the similarities between Xenopus and mammalian kidneys, highlight studies of CAKUT-causing genes in Xenopus and describe how common kidney diseases have been modeled successfully in this model organism. Additionally, we discuss several molecular pathways associated with kidney disease that have been studied in Xenopus and demonstrate why it is a useful model for studying human kidney diseases.

Keywords: CAKUT; CRISPR; Kidney; Nephron; Nephronophthisis; PKD; Xenopus.

Fig. 1.

Common malformations of the kidney found in CAKUT. Renal malformations resulting from inherited kidney diseases are depicted in colored boxes. The colors correspond to the color coding for genes whose loss results in the given phenotype. (1) Green represents renal cysts that are large and cover the majority of the kidney, as seen in renal dysplasia, multicystic dysplastic kidney (MCDK) and autosomal-dominant polycystic kidney disease (ADPKD). (2) Magenta represents a tumor, as seen in tuberous sclerosis and Wilms tumor. (3) Purple represents kidney agenesis (Box 1). (4) Teal represents renal hypoplasia, which is one of the most common CAKUT phenotypes. (5) Orange represents nephronophthisis, with maroon spots depicting corticomedullary cysts, which are generally small. (6) Blue represents the horseshoe kidney, where both kidneys are fused together. (7) Red represents ureter malformations and blockages, which result in urine backflow into the kidney (shown in yellow in the schematic). Genes listed in the key have been studied or are expressed in the Xenopus kidney. Numbers found in this figure in the bottom left corner that correspond to the aforementioned phenotypes can also be found in Table 1 under ‘Renal phenotype’.

Fig. 2.

Xenopus pronephric and human metanephric nephrons share conserved tubule segmentation patterns based on gene expression data. The schematic represents nephron segments, designated by different colors, in the mammalian metanephric nephron (top) and the Xenopus pronephric nephron (bottom). The glomus/glomerulus filters blood across capillary walls into the proximal tubule, which filters various wastes out of the body through the remaining distal and connecting tubules. There are noted differences between the glomus and glomerulus in that the glomus deposits blood filtrate into the coelomic cavity. Additionally, Xenopus does not have a loop of Henle (grayed out in human schematic) or a true collecting duct (grayed out in human schematic), but instead has a region analogous to the connecting tubule closest to the distal tubule of the mammalian metanephric nephron (Raciti et al., 2008).

Fig. 3.

Expression patterns are conserved between the human S-shaped body and the early Xenopus pronephros during development. Four different expression patterns (shown in different colors) of fundamental kidney proteins/mRNA were chosen to demonstrate the similarities between the developing human and Xenopus nephron. Schematics indicate where immunostaining of S-shaped body nephrons of week-16 to -17 human fetal kidneys is present (top) (Lindström et al., 2018), as well as in situ expression patterns of stage-33 Xenopus nephrons (bottom) (Xenbase.org). Schematics are positioned so that the proximal and distal regions of the human and Xenopus nephron expression patterns can be easily compared. The Xenopus kidney stage was chosen to match the approximate developmental time point of human S-shaped body nephrons, as both are representative of recently epithelialized nephrons. Note that pax2 is slightly more enriched at the nephrostomes in Xenopus (dark green).