A Role for Both V1a and V2 Receptors in Renal Heat Stress Injury Amplified by Rehydration with Fructose

Abstract

Chronic vasopressin secretion induced by recurrent mild heat stress exposure is significantly enhanced by limited rehydration with a fructose-containing beverage both in rodents and in humans. Moreover, this effect has been associated with upregulation of the polyol–fructokinase pathway and increased renal oxidative stress. Previously, we have shown that pharmacological inhibition of both V1a and V2 vasopressin receptors with conivaptan improved such renal alterations. The aim of this study was to evaluate the independent contributions of V1a and V2 receptors to the renal damage caused by mild heat stress and limited rehydration with a fructose-containing beverage. Osmotic minipumps were used to deliver either relcovaptan (0.64 mg/day) or tolvaptan (0.25 mg/day) in male Wistar rats for two weeks. Corresponding dilution vehicles were used as controls. To induce dehydration, rats were exposed to mild heat stress (37 °C for 1 h, Monday to Friday). All groups received a 10% fructose solution as a rehydration fluid for 2 h after mild heat stress. For the remainder of the day and on weekends, rats received tap water. The independent blockade of either the V1a or the V2 receptor prevented renal damage, reduced oxidative stress, and decreased plasma cortisol and systemic inflammation. However, the beneficial effects were regulated by different mechanisms. Tolvaptan inhibited polyol–fructokinase pathway overactivation, while relcovaptan prevented upregulation of the renin–angiotensin system and SGK1 expression. These data suggest that both V1a and V2 receptors participate in renal damage caused by heat stress-induced dehydration when fructose-containing beverages are used as rehydration fluids.

Current Hydration Habits: The Disregarded Factor for the Development of Renal and Cardiometabolic Diseases

“…There is also evidence that vasopressin activates the AR-F pathway. For example, a chronic vasopressin blockade with conivaptan or tolvaptan prevented the overexpression of the components of the AR-F pathway in recurrently mildly heat-dehydrated rats that were rehydrated with 10% fructose and protected them from kidney damage [ 106 , 118 ]. Thus, vasopressin also regulates the expression of AR-F enzymes, at least in the context of mild dehydration.…”

“…On the other hand, supplementation with antioxidants prevented the upregulation of AR-F enzymes in mildly dehydrated rats that were rehydrated with fructose [ 120 ] by preventing the nuclear translocation of the transcription factors responsible for AR and F, which are NFAT5 and ChREBP, respectively [ 120 ]. Since tolvaptan activates the nuclear factor erythroid 2-related factor (Nrf2) antioxidant pathway through the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) [ 121 ], this can explain why this treatment also prevented the up-regulation of AR-F enzymes in a state of mild dehydration [ 118 ]. Such data strongly suggest that increased oxidative stress plays an important role in the crosstalk between the vasopressin and AR-F pathways.…”

Restricted Water Intake and Hydration with Fructose-Containing Beverages during Infancy Predispose to Aggravate an Acute Renal Ischemic Insult in Adolescent Rats

“…The rats were again collected the next day for urine and euthanized for collecting blood and the left kidney, from which one-third was used to isolate proximal tubules and the remaining two-thirds were preserved in the same way as the right kidney. Tubular fractions were isolated using methods previously reported [ 24 , 40 ].…”

“…Experimental studies have shown that recurrent dehydration induces chronic overactivation of the polyol pathway and endogenous production of fructose in the renal cortex as well as the increased and continuous secretion of vasopressin [ 24 , 25 ]. Such effects lead to chronic tubulointerstitial damage [ 26 ].…”

“…Moreover, rehydration with a fructose-containing beverage worsened renal damage induced by dehydration [ 27 , 28 ]. In this context, the blockade of V1a and V2 vasopressin receptors with conivaptan prevented the overactivation of aldose reductase and fructokinase and provided nephroprotection [ 25 ], an effect that later was shown to be induced by the specific blockade of V2 receptor [ 24 ].…”