Chronic nicotine exposure reduces klotho expression and triggers different renal and hemodynamic responses inklotho-haploinsufficient mice

Abstract

The klotho gene, which encodes a single-pass transmembrane protein and a secreted protein, is expressed predominantly by the distal renal tubules and is related to calcium phosphorus metabolism, ion channel regulation, intracellular signaling pathways, and longevity. Klotho deficiency aggravates acute kidney injury and renal fibrosis. Exposure to nicotine also worsens kidney injury. Here, we investigated renal Klotho protein expression in a mouse model of chronic (28-day) nicotine exposure, in which mice received nicotine or vehicle (saccharine) in drinking water, comparing wild-type (WT) mice, klotho-haploinsufficient ( kl/+) mice, and their respective controls, in terms of the effects of that exposure. Nicotine exposure was associated with a significant decline in renal Klotho expression in WT and kl/+ mice as well as a reduction in the glomerular filtration rate in WT mice. Although plasma electrolytes were similar among the groups, fractional excretion of sodium was reduced in both nicotine-exposed groups. The nicotine-WT mice presented augmented baroreflex sensitivity to nitroprusside and augmented sympathetic cardiac modulation. However, nicotine- kl/+ mice presented higher plasma levels of urea and aldosterone together with a higher α-index (spontaneous baroreflex) and higher peripheral sympathetic modulation, as evaluated by spectral analysis. We can conclude that nicotine downregulates Klotho expression as well as that renal and autonomic responses to nicotine exposure are modified in kl/+ mice.

Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis

“…Therefore, most of our results regarding klotho expression are shown as transcripts by quantitative real-time PCR (most antibodies that are still available detect klotho the kidney, where it is most abundantly expressed in its full-length form; Refs. 7,49), since this was the most reliable and sensitive method. The ELISA, which is predominantly used to analyze soluble KL in human plasma, shows negative correlation of KL levels with age, consistent with previously discussed in vivo data characterizing KL as an antiaging protein (27,32,34).…”

Obesity aggravates acute kidney injury resulting from ischemia and reperfusion in mice

“…Kidney samples were homogenized as previously described 17 . Homogenates were centrifuged at 4000× g for 30 min at 4 °C, to remove nuclei and cell debris.…”

Xenobiotics Delivered by Electronic Nicotine Delivery Systems: Potential Cellular and Molecular Mechanisms on the Pathogenesis of Chronic Kidney Disease

“…The suppression of 11β-HSD2 by nicotine was dependent on the suppression of C/EBPβ (CCAAT/enhancer-binding protein-β) and activation of Akt protein kinase phosphorylation (pThr308Akt/PKB) by kidney cells [ 73 ]. Furthermore, exposure to oral nicotine for 28 days increased blood pressure, impaired glomerular filtration rate and fraction excretion of sodium, and augmented sympathetic cardiac modulation in mice with reduced renal Klotho gene expression [ 74 ]. The gene encodes a single-pass transmembrane protein expressed predominantly by the distal convoluted tubules in the kidneys and is related to calcium-phosphorus metabolism, ion channel regulation, intracellular signaling pathways, and longevity.…”

“…Although the harmful and direct effects of nicotine are well known and reported in clinical and experimental studies ( A ), other xenobiotics released by ENDS, such as acrolein, ultrafine particles (UFP), and flavorings possess the potential to trigger deleterious effects, leading to cumulative damages and favor CKD onset ( B ), however further data are required. The direct interaction of tobacco-released compounds with the endothelium increase reactive oxygen species (ROS), decreases endothelial nitric oxide species (eNOS) [ 73 , 74 , 126 , 127 , 128 , 129 , 170 ] and leads to an inflammatory response mediated or not by nicotinic receptor activation (nAChRs) or stress sensors receptors (TRPA1) [ 75 , 123 , 124 , 125 , 146 , 147 ], evoking endothelial dysfunction, impaired vascular relaxation, and increasing blood pressure. Directly or indirectly, these xenobiotics can impair glucose metabolism by affecting β islet cell homeostasis [ 85 , 86 , 90 ] and mitochondrial function in an ROS-dependent manner, culminating in insulin resistance and Diabetes Mellitus type II onset [ 95 , 100 , 135 ].…”