Month: February 2020

However, hypoxia-induced fibrosis may not be a vicious circle that further worsens oxygenation, but merely a way to maintain renal oxygenation by adapting oxygen consumption to the demand. Identical mechanisms might operate in animals. Animal models reporting hypoxia in CKD such as the 5/6 nephrectomy model may not have been carried out long enough to simulate the long-term adaptive changes in the kidney that might occur after several decades of chronic kidney disease or hypertension in humans. In line with this hypothesis, Priardarshy et al evaluated renal oxygenation six to eight weeks after remnant kidney creation, and found that renal oxygenation was not decreased, but rather increased in the remnant kidney. A similar observation was made in renal artery stenosis with a reduction of renal tissue oxygenation acutely but a good maintenance of tissue oxygenation in the chronically stenotic kidney. A role of renal handling of sodium in mediating oxygen consumption is supported by our observation that the medullary R2* response to furosemide differs between controls and hypertensives with a blunted response in hypertension and an even more marked reduction in CKD patients. In CKD, the markedly reduced response to furosemide can be explained by the reduced renal function leading to lower concentrations of furosemide within the kidney. However, this cannot be the explanation for hypertensive patients who had a comparable renal function as controls. Pratt et al have previously demonstrated ethnic differences in the response to furosemide ; to the best of our knowledge, differences in response to furosemide between normo-and hypertensive white subjects have not been reported previously. The blunted response to furosemide observed in hypertensive patients may be an indirect marker of the alterations in renal sodium handling in hypertension. Persons with essential hypertension have an increased proximal tubular reabsorption and a reduced distal delivery of sodium, which might blunt the effect of furosemide. Alternatively, there might be differences in mitochondrial metabolism and oxygen consumption in the thick ascending limb of Henle between hypertensive and normotensive subjects, in analogy with recently described differences between Dahl salt-sensitive rats and salt-resistant control strains. Our multivariate analysis enabled us to identify several new factors associated with renal tissue oxygenation. Thus, cortical R2* levels was positively and strongly associated with male gender. The relationship with male gender was robust and persisted in sensitivity analyses, and suggests that cortical oxygenation might be regulated differently in men and women. It may also provide some clues why renal function declines faster in men. The herein described association offers an alternative explanation in humans for to the relationship between badly controlled diabetes mellitus and adverse renal outcome.

We did, however, find gene body hypermethylation in CDH7, a type 2 classical cadherin from the cadherin superfamily, when comparing noninvasive to invasive NFAs. Further validation in a larger PA sample population is nevertheless warranted to identify and confirm genomic and epigenomic pathways involved in tumor invasion. Meanwhile, other epigenetic mechanisms should be explored in an effort to explain the character of PA invasion and prioritize genes associated with this clinically significant phenotype. The anterior pituitary gland secretes six known hormones that regulate homeostasis, including adrenocorticotropic hormone, growth hormone, prolactin, thyroid-stimulating hormone, follicle-stimulating hormone and luteinizing hormone. Clinically nonfunctioning PAs are not able to synthesize and/or secrete functional hormones, although in a majority of cases they nevertheless demonstrate positive immunostaining for LH, FSH, and/or the alpha-subunit. PAs are monoclonal in origin and typically benign tumors, suggesting they arise from expansion of single precursor cells that possess a unique proliferative advantage. These monoclonal adenomas therefore secrete specific hormones reflective of their differentiated cell of origin. In the current study, hierarchical clustering analysis readily separated somatotroph adenomas from nonfunctional adenomas, suggesting a potential role of DNA methylation in the differentiation and/or functional regulation of these tumors. Furthermore, an unexpected and interesting finding in the current study was that the functional corticotroph adenoma causing Cushing’s disease and the silent corticotroph adenoma clustered to the same hierarchical group. The exact mechanisms by which nonfunctioning PAs retain immunostaining but fail to produce clinically-active hormones remains to be determined. Our genome-scale screening of variability in DNA methylation between functional and nonfunctional PAs suggests that nonfunctional PAs are globally hypermethylated compared to functional ones. This finding is particularly interesting in that the most differentially methylated gene, KCNAB2, encodes a potassium ion-channel that has been previously implicated in endocrine function pertaining to insulin secretion. Pituitary cells resemble neurons and muscle fibers in that they also fire action potentials, which are mediated via expression of numerous voltage-gated sodium, potassium, calcium and chloride channels. These APs are accompanied by a rise in intracellular calcium and spontaneous electrical activity that drives intracellular calcium concentrations above the threshold for stimulus-secretion and stimulus-transcription coupling. KCNAB2 is a subunit of the shaker-related voltage dependent potassium channel, and upon binding to K + channel alpha subunits, contributes to regulation of channel excitability. In addition, KCNAB2 has been demonstrated as an functional aldoketoreductase.