Effect of Trehalose Supplementation on Autophagy and Cystogenesis in a Mouse Model of Polycystic Kidney Disease

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.

New Insights into the Mechanisms of Chaperon-Mediated Autophagy and Implications for Kidney Diseases

“…Macroautophagy has been shown to be suppressed in cell [101,102], zebra fish [103] and mouse models of PKD [65]. The renal mRNA expression of Atg genes, such as Atg12, Atg3, beclin1, and p62, is decreased in the PKD mouse model [104]. The role of CMA in this disease is still unknown.…”

Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

“…Autophagy helps maintain energy homeostasis and is activated when nutrients are lacking. Autophagy is impaired in PKD cells, nonorthologous murine models, and Pkd1 mutant zebrafish (5,(17)(18)(19). The central defect seems to be fusion of the autophagosome with the lysosome (i.e., autophagic flux) (18,19).…”

“…Correlatively, knockdown of the core autophagy protein Atg5 promotes cystogenesis, whereas treatment with the autophagy inducer Beclin-1 reduces cysts in a Pkd1 mutant zebrafish model (18). However, treatment with trehalose, a natural autophagy enhancer, is ineffective in ameliorating disease in a Pkd1 mutant model (17). Of note, mTORC1 is a known inhibitor of autophagy, and treatment with various rapalogs both enhances autophagy and reduces cystogenesis in PKD (5,18).…”

Two natural materials found to reduce adhesion formation in a rat uterine horn model

“…Many experimental studies have shown it to have a protective effect against adhesion formation [9], making it a frequently used clinical agent [10]. Its total absorption time from the abdomen is 2 weeks [11][12][13][14].…”

“…Trehalose (TRZ) is a natural disaccharide consisting of two glucose molecules [11,12]. It is used for organ preservation during transplantation, treatment of dry eye syndrome [12,13] and in different sectors such as the food and cosmetics industry [13]. The protection of biological molecules and the cell membrane can be explained by 3 theories: Water replacement, glass transformation, and chemical stability [15].…”