Are Saunas Beneficial Or Harmful For Autosomal Dominant Polycystic Kidney Disease? Examination With Model Mouse Ⅲ

IV Discussion

In this study, we investigated the effects of repeated sauna interventions in a PKD mouse model. The heat load used in this experiment was based on the temperature setting used in basic research on sauna therapy, which has been shown to have a clear effect on the cardiovascular system in humans20), 21). There was some variation between individuals with regard to 24-hour food intake or water intake, but no significant difference was observed. However, the body weight and weight gain at the end of the experiment were significantly lower in the TS group than in the SW group. In addition, the creatinine and BUN levels in the TS group were slightly higher than those in the control and SW groups, although the differences were not significant. Preliminary experiments confirmed that mice do not consume an adequate amount of tap water after sauna, but actively consume 4% sucrose water. Therefore, we provided 4% sucrose water to the mice to prevent dehydration from the sauna. However, the activity of the mice decreased immediately after sauna treatment, and no active drinking behavior was observed. The sauna, therefore, might have caused a physical overload until the mice were fully acclimatized to the heat. Moreover, they did not always receive the required fluid intake promptly after the sauna, and short-term dehydration following the sauna could lead to renal dysfunction.

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It is well known that many signal transduction and transcription factor pathways are altered in cystic kidneys compared to normal kidneys. Hsp90, which is a major heat shock protein and is abundant in cells, is highly expressed in ADPKD cells; cyst growth is reduced by reducing the function of Hsp90 with the Hsp90 inhibitor STA-2842 8). Regarding thermal therapy (WAON therapy) and Hsp90 expression, it has been confirmed that Hsp90 is upregulated through the activation of the Akt/eNOS/NO pathway22). However, as shown in Fig. 3C, the TS and SW groups showed significantly decreased Hsp90 expression compared to the control group, and the expression of Erk, which is related to cyst formation and proliferation, was also reduced23).

Vasopressin is a key factor that affects cyst growth in ADPKD24). Hypertonicity of the extracellular fluid caused by mild dehydration leads to an increase in vasopressin secretion25), 26). Although the effect of increased water intake on the progression of ADPKD has not been elucidated so far, sustained hydration by increased water intake is expected to benefit some patients with PKD, by limiting the detrimental effects of vasopressin on renal cyst growth27). However, there are no reports so far on the effects of sucrose water intake on ADPKD, although crosstalk between fructose (from 10% fructose water) and vasopressin has been shown to amplify dehydration-induced nephropathy28) . There is a low probability that a 4% sucrose water load exacerbates renal damage, judging from the rate of weight gain and low blood glucose levels in the SW group shown in Table 1. Furthermore, as shown in Fig. 1, 4% sucrose water intake was significantly higher than that of tap water, and urinary osmolality was low in both the TS and SW groups, suggesting that high water intake is an effective measure. Intake of 4% sucrose water after sauna was not a factor that worsened renal function, and active water intake may contribute to the decrease in Hsp90 expression. There were no significant changes observed in cyst growth after the 4-week sauna intervention, but longer-term interventions may show more obvious effects.

The expression of Hsp27 in the SW group was similar to that in the control group but was increased in the TS group. A major function of Hsp27 is the prevention of apoptosis29). We also reported that this action of Hsp27 is one of the mechanisms underlying the renoprotective effect of repeated mild systemic thermal stimulation on chronic kidney disease model mice13). Abnormal apoptosis observed in cyst-lining epithelial cells and noncystic tubular epithelial cells, as well as in cells within glomeruli, is believed to contribute to cyst extension in human PKD29)-31). Apoptosis of ADPKD undoubtedly plays a major role in disease development, but apoptosis is not the sole driver of cystogenesis. What is believed to establish the disease is a synergistic action of cell death, compensatory cell proliferation, and perturbed autophagy32), 33). In recent years, Yanda et al.34) have shown that Hsp27 described above, has an anti-apoptotic role and is involved in the growth of cysts in ADPKD. Heat-induced Hsp27 may not necessarily be involved in renal protection in ADPKD.

A limitation of this study is that a sufficient sample size could not be procured due to the high cost of the ADPKD mouse model, and hence, a clear test result could not be obtained. However, our findings indicate the likelihood of renal damage even with short-term sauna intervention in this study. There is a limitation on the reproducibility of these results in humans because these data were obtained from PKD model mice. However, in order to prevent renal damage from the sauna, drinking water immediately after the sauna is considered helpful even in clinical situations.

Figure 6 shows the results of the study. In ADPKD, the MEK/ERK pathway activity (Fig. 6, solid lines: active pathways) caused by the intracellular Ca2+ concentration was inferior (Fig. 6, dotted lines: diminished pathways) to PKD gene mutations, and as an effect of cAMP via vasopressin receptor 2, these two pathways of cell proliferation by the B-Raf/MEK/ERK pathway (Fig. 6, solid lines: active pathways) are related35). Mutations in the PKD genes (PKD1 and PKD2) disrupt intracellular Ca2+ regulation. Epithelial cells isolated from human ADPKD kidney cysts have lower levels of intracellular Ca2+ than cells in normal renal tissue. Disruption of intracellular Ca2+ homeostasis and Ca2+ signaling reduces Akt and activates the MEK/ERK pathway36) . Arginine vasopressin activates vasopressin V2 receptors and increases cAMP synthesis37). In PKD cells, cAMP activates the B-Raf/MEK/ERK pathway and affects cyst growth38), 39)

In this experiment, the heat load interval of the TS group was set to 2 to 3 days, and the large amount of water intake for the SW group was carried out at the same frequency and time as the TS group. A previous study indicated that a single sufficient heat load increased Hsp expression in renal tissue; however, from 8 h to 24 h, it reached its peak and returned to the baseline at 72 h40). A large amount of water intake decreases V2 receptor expression in PKD kidney tissue and inhibits the B-Raf/MEK/ERK pathway27). The heat and water loading protocols in this experiment were not sufficient to obtain a clear effect for ADPKD.

V Conclusion

Results of these experiments have suggested that the heat load on the body caused by sauna carries a risk of temporary dehydration and associated renal dysfunction, and may stimulate cyst formation and proliferation with increased expression of Hsp27. On the other hand, if an appropriate amount of water is ingested immediately after sauna, dehydration may be prevented and cyst growth can be suppressed. Based on the results of this study, the following three factors are considered important with regard to saunas for ADPKD. 1. The fluctuations in food intake and weight should be regularly checked. 2. The elevation of the core body temperature, and the retention time of the elevated core body temperature, should be such that the heat load is not high enough to exhaust physical strength. 3. An adequate amount of water should be consumed immediately after the sauna. By taking these steps, it is expected that sauna therapy can help arrest the progression of ADPKD, and mitigate the decrease in renal function due to heat load.

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