Mechanisms of Cyst Development in Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease is the most common inherited cause of end-stage kidney disease worldwide. Most cases result from mutation of either of 2 genes, PKD1 and PKD2, which encode proteins that form a probable receptor/channel complex. Studies suggest that a loss of function of the complex below an indeterminate threshold triggers cyst initiation, which ultimately results in dysregulation of multiple metabolic processes and downstream pathways and subsequent cyst growth. Noncell autonomous factors may also promote cyst growth. In this report, we focus primarily on the process of early cyst formation and factors that contribute to its variability with brief consideration of how new studies suggest this process may be reversible.

Chronic Exercise Protects against the Progression of Renal Cyst Growth and Dysfunction in Rats with Polycystic Kidney Disease.

INTRODUCTION: Polycystic kidney disease (PKD) is a genetic disorder characterized by the progressive enlargement of renal epithelial cysts and renal dysfunction. Previous studies have reported the beneficial effects of chronic exercise on chronic kidney disease. However, the effects of chronic exercise have not been fully examined in PKD patients or models. The effects of chronic exercise on the progression of PKD were investigated in a polycystic kidney (PCK) rat model. METHODS: Six-week-old male PCK rats were divided into a sedentary group and an exercise group. The exercise group underwent forced treadmill exercise for 12 wk (28 m·min-1, 60 min·d-1, 5 d·wk-1). After 12 wk, renal function and histology were examined, and signaling cascades of PKD progression, including arginine vasopressin (AVP), were investigated. RESULTS: Chronic exercise reduced the excretion of urinary protein, liver-type fatty acid-binding protein, plasma creatinine, urea nitrogen, and increased plasma irisin and urinary AVP excretion. Chronic exercise also slowed renal cyst growth, glomerular damage, and interstitial fibrosis and led to reduced Ki-67 expression. Chronic exercise had no effect on cAMP content but decreased the renal expression of B-Raf and reduced the phosphorylation of extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), and S6. CONCLUSION: Chronic exercise slows renal cyst growth and damage in PCK rats, despite increasing AVP, with the downregulation of the cAMP/B-Raf/ERK and mTOR/S6 pathways in the kidney of PCK rats.

Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease.

Polycystic liver disease (PLD) is a hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with the activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats. PCK rats were randomly divided into a control (Con) group and a metformin-treated (Met) group. The Met group was treated orally with metformin in drinking water. After 12 wk, liver function, histology, and signaling cascades of PLD were examined in the groups. Metformin did not affect the body weight or liver weight, but it reduced liver cyst formation, cholangiocyte proliferation, and fibrosis around the cyst. Metformin increased the phosphorylation of AMPK and tuberous sclerosis complex 2 and decreased the phosphorylation of mammalian target of rapamycin, S6, and extracellular signal-regulated kinase and the expression of cystic fibrosis transmembrane conductance regulator, aquaporin I, transforming growth factor-ß, and type 1 collagen without changes in apoptosis or collagen degradation factors in the liver. Metformin slows the development of cyst formation and fibrosis with the activation of AMPK and inhibition of signaling cascades responsible for cellular proliferation and fibrosis in the liver of PCK rats.NEW & NOTEWORTHY This study indicates that metformin, an indirect AMPK activator slows liver cyst formation and fibrosis in PLD rat model. Metformin attenuates excessive cell proliferation in the liver with the inactivation of mTOR and ERK pathways. Metformin also reduces the expression of proteins responsible for cystic fluid secretion and liver fibrosis. Metformin and AMPK activators may be potent drugs for polycystic liver disease.

Effects of Long-Term Exercise on Liver Cyst in Polycystic Liver Disease Model Rats.

BACKGROUND: Polycystic liver disease (PLD) is a hereditary liver disease with progressive enlargement of fluid-filled liver cysts, which causes abdominal discomfort and worsens quality of life. Long-term exercise has beneficial effects in various organs, but the effects of long-term exercise on PLD are unclear. Therefore, the aim of this study was to investigate whether long-term exercise inhibits liver cyst formation and fibrosis. METHODS: Polycystic kidney (PCK) rats, a model of PLD, were randomly divided into a sedentary group and a long-term exercise group, which underwent treadmill running for 12 wk (28 m·min, 60 min·d, 5 d·wk). Sprague-Dawley (SD) rats were set as a control group. After 12 wk, exercise capacity, histology, and signaling cascades of PLD were examined. RESULTS: Compared with control SD rats, PCK rats showed a low exercise capacity before exercise protocol. After 12 wk, the exercise improved the exercise capacity and ameliorated liver cyst formation and fibrosis. The exercise significantly decreased the number of Ki-67-positive cells; the expression of cystic fibrosis transmembrane conductance regulator, aquaporin 1, transforming growth factor ß, and type 1 collagen; and the phosphorylation of extracellular signal-regulated kinase, mammalian target of rapamycin and S6. It also increased the phosphorylation of AMP-activated protein kinase in the liver of PCK rats. CONCLUSIONS: The present results indicated that long-term moderate-intensity exercise ameliorates liver cyst formation and fibrosis with the inhibition of signaling cascades responsible for cellular proliferation and fibrosis in PCK rats.