Animal Models for Human Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is a hereditary disorder with abnormal cellular proliferation, fluid accumulation in numerous cysts, remodeling of extracellular matrix, inflammation, and fibrosis in the kidney and liver. The two major types of PKD show autosomal dominant (ADPKD) or autosomal recessive inheritance (ARPKD). ADPKD is one of the most common genetic diseases, with an incidence of 1:500-1,000. Approximately 50% of patients with ADPKD develop end-stage renal disease (ESRD) by the age of 60. On the other hand, ARPKD is relatively rare, with an incidence of approximately 1:20,000-40,000. ARPKD is diagnosed early in life, often prenatally. The gene products responsible for ADPKD and ARPKD distribute in primary cilia and are thought to control intercellular Ca 2+ . Two types of animal model of PKD have been established: spontaneous hereditary models identified by the typical manifestations of PKD and gene-engineered models established by modification of human orthologous genes. Both types of animal models are used to study the mechanism of cystogenesis and efficacy of medical treatments. In PKD progression, critical roles of signaling pathways including MAPK, mTOR, and PPAR-γ have been discovered with these models. Therefore, experimental animal models are indispensable for investigating molecular mechanisms of PKD onset and progression as well as potential therapeutic treatments.

MALDI imaging MS reveals candidate lipid markers of polycystic kidney disease

“…However, little is known about GSL levels in ARPKD: In contrast to elevations of some acidic GSLs in ADPKD models, sulfatide levels, for instance, are decreased in cpk/cpk mice, an ARPKD model ( 15 ). In contrast to these mice, the disease gene in PCK rats is orthologous to the polycystic kidney and hepatic disease 1 gene affected in human ARPKD ( 16 ). Several characteristics of human disease are manifest in homozygous PCK rats ( 17 ), allowing for investigation of the molecular pathogenesis and testing of experimental therapeutics ( 18 ).…”

Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptor γ agonists

“…In a slow-progressing model, the Han:SPRD rat, which demonstrates proximal cystic disease, rosiglitazone at 10 mg/kg BW/day decreased the renal cystic burden, protected renal function, and prolonged survival in short-term (8 weeks post weaning) and long-term (6 months post weaning) studies [27] . The PCK rat model is a slowly progressing model that has been used extensively for preclinical testing [28,29] . In a previous study, the PCK rat was treated with pioglitazone for either 7 or 14 weeks directly after weaning [5] ( Table 1).…”

Tolvaptan Delays the Onset of End-Stage Renal Disease in a Polycystic Kidney Disease Model by Suppressing Increases in Kidney Volume and Renal Injury

“…Tolvaptan Delays the Onset of ESRD in PKD Animal Model disease, the lifespans of these animals are .1 year (Doctor et al, 2010;Nagao et al, 2012).…”

“…To solve this issue, we conducted the longterm study (to 29 weeks of age) to investigate the time course of the effects of tolvaptan on kidney enlargement, measured by magnetic resonance imaging (MRI), and mortality as an index of ESRD using DBA/2FG-pcy (pcy) mice, which exhibit autosomal recessive cystic kidney disease caused by a missense mutation in NPHP3, which is responsible for adolescent nephronophthisis (Nagao et al, 1991;Takahashi et al, 1991;Olbrich et al, 2003). In pcy mice, cysts are derived from distal tubules, and whole-nephron segments become diffusely occupied by cysts accompanying disease progression by 30 weeks of age, often with the occurrence of ESRD (Nagao et al, 2012).…”