Table 3.

Examples of zebrafish and mouse models that have differentially contributed to our understanding of the pathomechanisms of human inherited kidney disease

Human Kidney DiseaseZebrafishMouse
Glomerulopathies
 Alport syndromeThe zebrafish mutant dragnet (alias col4a5) fails to recapitulate the human phenotype. Loss of col4a5 expression leads to defects in the laminar organization of the retinotectal projection, but no glomerular phenotype is observable (126)Col4a3 knockout mouse model of autosomal Alport syndrome is characterized by progressive GN with microhematuria and proteinuria, consistent with the human disease, and focal multilaminated thickening and thinning of the glomerular basement membrane starting at 4 wk. End stage kidney failure happens at 14 wk with fibrotic glomeruli and collapsed capillaries (57). The finding that these mice display an upregulation of miR-21 and that inhibition of miR-21 slows kidney disease progression has identified a promising therapeutic target (58)
 Nephrotic syndrome type 1 and 2The functions of the podocyte-specific proteins nephrin (nphs1) and podocin (nphs2) are highly conserved between the zebrafish pronephros and mammalian metanephros. Knockdown of nphs1 and nphs2 results in abnormal slit diaphragm and foot process architecture and in altered glomerular filtration (53)Nphs1−/− and Nphs2−/− mice are born alive but die within 24 h and 5 wk, respectively, indicating a more severe phenotype when compared with human (127). Nphs2−/− mice develop diffuse mesangial sclerosis, indicating that, during glomerulogenesis, absence of podocin may lead to important alterations in the podocyte-endothelial-mesangial crosstalk (79)
 Nephrotic syndrome type 4Knockdown of Wilms tumor 1a (wt1a) in zebrafish embryos leads to defects in podocyte development with effacement of foot processes, abnormalities in the slit diaphragm, and dysfunctional glomerular filtration, as assessed by injected dextran clearance rate (47)Wt1 null mice are embryonic lethal, showing failure of kidney and gonad development. Metanephric mesenchyme cells are apoptotic and the ureteric bud does not stem from the Wolffian duct (128)
Tubulopathies/kidney ciliopathies
 Autosomal dominant tubulointerstitial kidney disease–UMODUromodulin (umod) morphants do not display kidney development defects, nor increased susceptibility to nephrotoxins, nor significant alterations in glomerular or tubule gene expression (129), perhaps consistently with a lack of a loop of Henle in the zebrafishUmod null mice do not display anatomic or functional kidney alterations, but have altered levels of transporters in the loop of Henle (60)
 CystinosisMutant ctns zebrafish exhibit cystine accumulation, altered tubular reabsorption, and glomerular permeability, in line with the human phenotype (130)Ctns−/− mice on the 129Sv × C57BL/6 genetic background, despite elevated kidney cystine levels, do not show an overt kidney phenotype (131), whereas Ctns−/− on the C57BL/6 background develop histologic kidney lesions but no clear glomerulopathy (78)
  ADPKDZebrafish embryos microinjected with mRNA, encoding the C-terminal cytoplasmic portion of polycystin-1, form pronephric and liver cysts at 3 d post-fertilization, demonstrating the importance of pkd1 dosage to maintain pronephric and liver architecture in the zebrafish embryos (132). pkd2 was found mutated in an insertional mutagenic screen for zebrafish mutant embryos that displayed cystic pronephros phenotypes (41)Pkd1 and Pkd2 null mice are embryonic lethal, whereas heterozygous mice are viable and progressively develop kidney cysts (62). Pkd2WS25 mice harbor an unstable allele. Localized absence of polycystin-2 in Pkd2WS25 cyst-lining epithelia implies a somatic loss of Pkd2 in kidney cysts (62) and argues in favor of a two-hit hypothesis for ADPKD pathogenicity; but the increased proliferation in kidney noncystic, polycystin-2–positive epithelia indicates that haploinsufficiency of Pkd2 is sufficient to cause cell proliferation in early polycystic kidney disease (64). The conditional Pkd1cond/cond mouse shows a variable onset of cystic kidney disease which depends on the time of genetic inactivation of Pkd1, indicating that the pathologic consequences of inactivation depend on the maturation status of the kidney (133)
 Nephronophthisis type 3Knockdown of nphp3 in the zebrafish embryo causes hydrocephalus and body symmetry defects due to ciliary abnormalities at the Kupffer vesicle (134), a temporary developmental organ of left-right axis determinationThe pcy mouse is an ortholog of NPHP3 and a slowly progressive model of cystic kidney disease, with kidney enlargement arising at 8 wk and thickened basement membrane (135). Pcy mice display a significant increase in kidney cAMP concentration and in the expression of V2R and AQP2, which is a gene positively regulated by cAMP (69)
 Nephronophthisis type 6Knockdown of cep290 in zebrafish embryos results in retinal and brain defects as well as cyst formation in the pronephros, resembling the clinical features of patients with Joubert syndrome (136). cep290 morphant fish exhibit increased levels of γh2ax, a marker of DNA damage response signaling, suggesting a role for DNA damage or DNA damage response signaling in the pathophysiology of CEP290-associated kidney disease (137)The Cep290−/− mice on a 129/Ola background are viable and present a mild kidney phenotype, with collecting duct small kidney cysts but no significant kidney enlargement, in line with a NPHP phenotype. Abnormalities in ciliary phenotype and in Hedgehog signaling are observable in cystic epithelia (80). Cep290−/− mice on a C57BL/6 background present severe hydrocephalus and are lethal (80,138), highlighting the possible contribution of genetic modifiers in the definition of the phenotype
 Nephronophthisis type 9Knockdown of nek8 in zebrafish embryos leads to cyst formation and abnormal cardiac looping. Similar phenotypes are observed when zebrafish inversin (inv, orthologous of the genetic cause of NPHP2) is knocked down. Overexpression of nek8 through mRNA microinjection rescues these phenotypes in inv morphants, indicating that nek8 may act downstream of inv (139)The jck mouse genetically is an orthologous model of NPHP9, with mutations in the Nek8 gene. Phenotypically it resembles ADPKD, with significantly enlarged kidneys at 4 wk. Kidneys present high cAMP levels and elevated PCNA staining in cyst-lining epithelia, revealing a proliferative phenotype and promising therapeutic targets (140142)
  • ADPKD, autosomal dominant polycystic kidney disease; NPHP, nephronophthisis; V2R, vasopressin V2 receptor; AQP2, aquaporin-2; PCNA, proliferating cell nuclear antigen.