Abstract
Autophagy impairment has been demonstrated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) and could be a new target of treatment. Trehalose is a natural, nonreducing disaccharide that has been shown to enhance autophagy. Therefore, we investigated whether trehalose treatment reduces renal cyst formation in a Pkd1-hypomorphic mouse model. Pkd1 miRNA transgenic (Pkd1 miR Tg) mice and wild-type littermates were given drinking water supplemented with 2% trehalose from postnatal day 35 to postnatal day 91. The control groups received pure water or 2% sucrose for the control of hyperosmolarity. The effect on kidney weights, cystic indices, renal function, cell proliferation, and autophagic activities was determined. We found that Pkd1 miR Tg mice had a significantly lower renal mRNA expression of autophagy-related genes, including atg5, atg12, ulk1, beclin1, and p62, compared with wild-type control mice. Furthermore, immunohistochemical analysis showed that cystic lining cells had strong positive staining for the p62 protein, indicating impaired degradation of the protein by the autophagy-lysosome pathway. However, trehalose treatment did not improve reduced autophagy activities, nor did it reduce relative kidney weights, plasma blood urea nitrogen levels, or cystatin C levels in Pkd1 miR Tg mice. Histomorphological analysis revealed no significant differences in the renal cyst index, fibrosis score, or proliferative score among trehalose-, sucrose-, and water-treated groups. Our results demonstrate that adding trehalose to drinking water does not modulate autophagy activities and renal cystogenesis in Pkd1-deficient mice, suggesting that an oral supplement of trehalose may not affect the progression of ADPKD.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and loss of renal function with age, accounting for up to 10% of patients entering treatment for end-stage renal disease [1]
We utilized Pkd1 miR Tg mice, an orthologous mouse model mimicking the natural progression of ADPKD, to test the potential therapeutic efficacy of trehalose [28]
The oral administration of trehalose did not decrease the fraction of kidney weight of Pkd1 miR Tg mice compared with those in the mice fed drinking water supplemented with 2% sucrose or pure drinking water
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and loss of renal function with age, accounting for up to 10% of patients entering treatment for end-stage renal disease [1]. A seminal study showed that autophagy activation through various autophagy enhancers may reduce cystogenesis in a zebrafish model of PKD1 [16], suggesting that autophagy activation may be a new treatment strategy for ADPKD. Trehalose enhanced autophagy and reduced abnormal protein aggregation in the brain tissue of mice with Huntington’s disease [24,25]. We tested the hypothesis that trehalose supplementation decreases renal cyst formation and progression in a mouse model of ADPKD. We determined whether autophagy is abnormally regulated during the progression of polycystic kidney disease
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