Aging is associated with an elevated risk of heat-related mortality and morbidity, attributed, in part, to declines in thermoregulation. However, comparisons between young and older adults have been ...limited to brief exposures (1-4 h), which may not adequately reflect the duration or severity of the heat stress experienced during heat waves. We therefore evaluated physiological responses in 20 young (19-31 yr; 10 females) and 39 older (61-78 yr; 11 females) adults during 9 h of rest at 40°C and 9% relative humidity. Whole body heat exchange and storage were measured with direct calorimetry during the first 3 h and final 3 h. Core temperature (rectal) was monitored continuously. The older adults stored 88 kJ 95% confidence interval (CI): 29, 147 more heat over the first 3 h of exposure (
= 0.006). Although no between-group differences were observed after 3 h young: 37.6°C (SD 0.2°C) vs. older: 37.7°C (0.3°C);
= 0.216, core temperature was elevated by 0.3°C 0.1, 0.4 (adjusted for baseline) in the older group at
37.6°C (0.2°C) vs. 37.9°C (0.2°C);
< 0.001 and by 0.2°C 0.0, 0.3 at
37.7°C (0.3°C) vs. 37.8°C (0.3°C), although the latter comparison was not significant after multiplicity correction (
= 0.061). Our findings indicate that older adults sustain greater increases in heat storage and core temperature during daylong exposure to hot dry conditions compared with their younger counterparts. This study represents an important step in the use of ecologically relevant, prolonged exposures for translational research aimed at quantifying the physiological and health impacts of hot weather and heat waves on heat-vulnerable populations.
We found greater increases in body heat storage and core temperature in older adults than in their younger counterparts during 9 h of resting exposure to hot dry conditions. Furthermore, the age-related increase in core temperature was exacerbated in older adults with common heat-vulnerability-linked health conditions (type 2 diabetes and hypertension). Impairments in thermoregulatory function likely contribute to the increased risk of heat-related illness and injury seen in older adults during hot weather and heat waves.
Prolonged work in the heat increases the risk of acute kidney injury (AKI) in young men. Whether aging and age-associated chronic disease may exacerbate the risk of AKI remains unclear.
We evaluated ...plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum kidney injury molecule-1 (KIM1) before and after 180 min of moderate-intensity work (200 W/m
) in temperate (wet-bulb globe temperature WBGT 16 °C) and hot (32 °C) environments in healthy young (n = 13, 22 years) and older men (n = 12, 59 years), and older men with type 2 diabetes (T2D; n = 9, 60 years) or hypertension (HTN; n = 9, 60 years).
There were no changes in NGAL or KIM1 concentrations following prolonged work in temperate conditions in any group. Despite a similar work tolerance, the relative change in NGAL was greater in the older group when compared to the young group following exercise in the hot condition (mean difference + 82 ng/mL; p < 0.001). Baseline concentrations of KIM1 were ~ 22 pg/mL higher in the older relative to young group, increasing by ~ 10 pg/mL in each group after exercise in the heat (both p ≤ 0.03). Despite a reduced work tolerance in the heat in older men with T2D (120 ± 40 min) and HTN (108 ± 42 min), elevations in NGAL and KIM1 were similar to their healthy counterparts.
Age may be associated with greater renal stress following prolonged work in the heat. The similar biomarker responses in T2D and HTN compared to healthy older men, alongside reduced exercise tolerance in the heat, suggest these individuals may exhibit greater vulnerability to heat-induced AKI if work is prolonged.
Health agencies, including the U.S. Centers for Disease Control and Prevention and the World Health Organization, recommend that heat-vulnerable older adults without home air-conditioning should ...visit cooling centers or other air-conditioned locations (e.g., a shopping mall) during heat waves. However, experimental evidence supporting the effectiveness of brief air-conditioning is lacking.
We evaluated whether brief exposure to an air-conditioned environment, as experienced in a cooling center, was effective for limiting physiological strain in older adults during a daylong laboratory-based heat wave simulation.
Forty adults 64-79 years of age underwent a 9-h simulated heat wave (heat index: 37°C) with (cooling group,
) or without (control group,
) a cooling intervention consisting of 2-h rest in an air-conditioned room (
, hours 5-6). Core and skin temperatures, whole-body heat exchange and storage, cardiovascular function, and circulating markers of acute inflammation were assessed.
Core temperature was 0.8°C (95% CI: 0.6, 0.9) lower in the cooling group compared with the control group at the end of the cooling intervention (
; hour 6), and it remained 0.3°C (95% CI: 0.2, 0.4) lower an hour after returning to the heat (
; hour 7). Despite this, core temperatures in each group were statistically equivalent at hours 8 and 9, within
(
). Cooling also acutely reduced demand on the heart and improved indices of cardiovascular autonomic function (
); however, these outcomes were not different between groups at the end of exposure (
).
Brief air-conditioning exposure during a simulated heat wave caused a robust but transient reduction in core temperature and cardiovascular strain. These findings provide important experimental support for national and international guidance that cooling centers are effective for limiting physiological strain during heat waves. However, they also show that the physiological impacts of brief cooling are temporary, a factor that has not been considered in guidance issued by health agencies. https://doi.org/10.1289/EHP11651.
Purpose
Klotho is a cytoprotective protein that increases during acute physiological stressors (e.g., exercise heat stress), although age-related declines in klotho may underlie cellular ...vulnerability to heat stress. The present study aimed to compare serum klotho in healthy older men and men with type 2 diabetes (T2D) or hypertension (HTN) during prolonged exercise in temperate or hot conditions.
Methods
We evaluated serum klotho in 12 healthy older men (mean SD; 59 years 4), 10 men with HTN (60 years 4), and 9 men with T2D (60 years 5) before and after 180 min of moderate-intensity (fixed metabolic rate of 200 W/m
2
; ~ 3.4 METs) exercise and 60 min of recovery in temperate (wet-bulb globe temperature (WBGT) 16 °C) and hot (WBGT 32 °C) environments. Core temperature (rectal), heart rate (HR), and heart rate reserve (HRR) were measured continuously while klotho was measured at the end of baseline, exercise, and recovery.
Results
Total exercise duration was reduced during the hot condition in older men with HTN and T2D than healthy older men (both p ≤ 0.049), despite similar core temperatures, HR, and HRR. Klotho was higher than rest following exercise in the heat in healthy older men (+ 191 pg/mL 189; p < 0.001) and responses were greater (p = 0.036) than men with HTN (+ 118 pg/mL 49; p = 0.030), although klotho did not increase in men with T2D (+ 4 pg/mL 71; p ≥ 0.638).
Conclusion
Given klotho’s role in cytoprotection, older men with HTN and especially T2D may be at increased cellular vulnerability to prolonged exercise or physically demanding exercise in the heat.
Chronic high blood pressure (hypertension) is the most common disease in the Unites States. While several classes of drugs exist to treat it, many patients (up to 10 million Americans) respond poorly ...to therapy, even when multiple classes are used. Recent evidence suggests that a significant portion of patients will always remain hypertensive despite maximum therapy with the drugs currently available. Therefore, there is a pressing need to develop novel antihypertensive agents. One limitation has been the identification of new targets, a limitation that has been overcome by recent insights into the mechanisms underlying monogenic forms of hypertension. The disease familial hyperkalemic hypertension is caused by mutations in with-no-lysine (WNK) kinases 1 and 4 and in cullin-3 and kelch-like 3, components of an E3 ubiquitin ligase complex that promotes WNK kinase degradation. The study of the mechanisms by which this pathway regulates blood pressure has identified several candidates for the development of new antihypertensive agents. This pathway is particularly attractive since its inhibition may not only reduce renal sodium reabsorption along multiple segments but may also reduce vascular tone. Here, we will describe the mechanisms by which this pathway regulate blood pressure and discuss the potential of targeting it to develop new antihypertensive drugs.
Excessive renal efferent sympathetic nerve activity contributes to hypertension in many circumstances. Although both hemodynamic and tubular effects likely participate, most evidence supports a major ...role for α-adrenergic receptors in mediating the direct epithelial stimulation of sodium retention. Recently, it was reported, however, that norepinephrine activates the thiazide-sensitive NaCl cotransporter (NCC) by stimulating β-adrenergic receptors. Here, we confirmed this effect and developed an acute adrenergic stimulation model to study the signaling cascade. The results show that norepinephrine increases the abundance of phosphorylated NCC rapidly (161% increase), an effect largely dependent on β-adrenergic receptors. This effect is not mediated by the activation of angiotensin II receptors. We used immunodissected mouse distal convoluted tubule to show that distal convoluted tubule cells are especially enriched for β₁-adrenergic receptors, and that the effects of adrenergic stimulation can occur ex vivo (79% increase), suggesting they are direct. Because the 2 protein kinases, STE20p-related proline- and alanine-rich kinase (encoded by STK39) and oxidative stress-response kinase 1, phosphorylate and activate NCC, we examined their roles in norepinephrine effects. Surprisingly, norepinephrine did not affect STE20p-related proline- and alanine-rich kinase abundance or its localization in the distal convoluted tubule; instead, we observed a striking activation of oxidative stress-response kinase 1. We confirmed that STE20p-related proline- and alanine-rich kinase is not required for NCC activation, using STK39 knockout mice. Together, the data provide strong support for a signaling system involving β₁-receptors in the distal convoluted tubule that activates NCC, at least in part via oxidative stress-response kinase 1. The results have implications about device- and drug-based treatment of hypertension.
Activation of the Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2) and the Na(+)-Cl(-)-cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conserved N-terminal threonine and serine ...residues, but the kinase pathways that mediate this action of vasopressin are not well understood. Two homologous Ste20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor-specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.
K
deficiency stimulates renal salt reuptake via the Na
-Cl
cotransporter (NCC) of the distal convoluted tubule (DCT), thereby reducing K
losses in downstream nephron segments while increasing NaCl ...retention and blood pressure. NCC activation is mediated by a kinase cascade involving with no lysine (WNK) kinases upstream of Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). In K
deficiency, WNKs and SPAK/OSR1 concentrate in spherical cytoplasmic domains in the DCT termed "WNK bodies," the significance of which is undetermined. By feeding diets of varying salt and K
content to mice and using genetically engineered mouse lines, we aimed to clarify whether WNK bodies contribute to WNK-SPAK/OSR1-NCC signaling. Phosphorylated SPAK/OSR1 was present both at the apical membrane and in WNK bodies within 12 h of dietary K
deprivation, and it was promptly suppressed by K
loading. In WNK4-deficient mice, however, larger WNK bodies formed, containing unphosphorylated WNK1, SPAK, and OSR1. This suggests that WNK4 is the primary active WNK isoform in WNK bodies and catalyzes SPAK/OSR1 phosphorylation therein. We further examined mice carrying a kidney-specific deletion of the basolateral K
channel-forming protein Kir4.1, which is required for the DCT to sense plasma K
concentration. These mice displayed remnant mosaic expression of Kir4.1 in the DCT, and upon K
deprivation, WNK bodies developed only in Kir4.1-expressing cells. We postulate a model of DCT function in which NCC activity is modulated by plasma K
concentration via WNK4-SPAK/OSR1 interactions within WNK bodies.
High-resolution single-nucleus RNA-sequencing data indicate a clear separation between primary sites of calcium and magnesium handling within distal convoluted tubule (DCT). Both DCT1 and DCT2 ...express Slc12a3, but these subsegments serve distinctive functions, with more abundant magnesium-handling genes along DCT1 and more calcium-handling genes along DCT2. The data also provide insight into the plasticity of the distal nephron-collecting duct junction, formed from cells of separate embryonic origins. By focusing/changing gradients of gene expression, the DCT can morph into different physiological cell states on demand.
The distal convoluted tubule (DCT) comprises two subsegments, DCT1 and DCT2, with different functional and molecular characteristics. The functional and molecular distinction between these segments, however, has been controversial.
To understand the heterogeneity within the DCT population with better clarity, we enriched for DCT nuclei by using a mouse line combining "Isolation of Nuclei Tagged in specific Cell Types" and sodium chloride cotransporter-driven inducible Cre recombinase. We sorted the fluorescently labeled DCT nuclei using Fluorescence-Activated Nucleus Sorting and performed single-nucleus transcriptomics.
Among 25,183 DCT cells, 75% were from DCT1 and 25% were from DCT2. In addition, there was a small population (<1%) enriched in proliferation-related genes, such as Top2a , Cenpp , and Mki67 . Although both DCT1 and DCT2 expressed sodium chloride cotransporter, magnesium transport genes were predominantly expressed along DCT1, whereas calcium, electrogenic sodium, and potassium transport genes were more abundant along DCT2. The transition between these two segments was gradual, with a transitional zone in which DCT1 and DCT2 cells were interspersed. The expression of the homeobox genes by DCT cells suggests that they develop along different trajectories.
Transcriptomic analysis of an enriched rare cell population using a genetically targeted approach clarifies the function and classification of distal cells. The DCT segment is short, can be separated into two subsegments that serve distinct functions, and is speculated to derive from different origins during development.
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