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Research in Veterinary Science Apr 2020Fifty-three privately owned dogs were included in the study. Ultrasonography of the kidneys was performed ante mortem. All the dogs died or were euthanized for reasons...
Fifty-three privately owned dogs were included in the study. Ultrasonography of the kidneys was performed ante mortem. All the dogs died or were euthanized for reasons unrelated to this study. Histopathology of both kidneys was performed, and a degeneration and an inflammation score ranging from zero to two was assigned by consensus between two pathologists. A numerical score based on a three level semi-quantitative scale (0, 0.5, 1) was assigned by consensus between two of the authors to the following ultrasonographic abnormalities: cortico-medullary definition, echogenicity of the renal cortex, echogenicity of the medulla, renal shape, cysts, scars, mineralizations, subcapsular perirenal fluid accumulation, pyelectasia. The scores deriving from the consensus were summed to create a summary index called renal ultrasound score (RUS). Statistically significant differences in cortico-medullary definition, echogenicity of the renal cortex, echogenicity of the medulla, renal shape, scars and pyelectasia were evident between the degeneration score groups. There were significantly different distributions of cortico-medullary definition, renal shape and scars between the inflammatory score groups. There were statistically significant differences in the RUS between the degenerative score groups (F = 24.154, p-value<.001). Post-hoc tests revealed significant differences between all groups. There were no significant differences in the RUS between the inflammatory score groups (F = 1.312, p-value = .264). Post-hoc tests revealed no significant differences between groups. The results of the present study suggest that the number and severity of the ultrasonographic abnormalities are correlated with the severity of the kidney degeneration. On the other hand, inflammation showed poor influence on the ultrasonographic appearance of the kidneys.
Topics: Animals; Dog Diseases; Dogs; Female; Kidney; Kidney Diseases; Male; Ultrasonography
PubMed: 31931264
DOI: 10.1016/j.rvsc.2020.01.003 -
European Journal of Immunology Aug 2022Renal immune cells serve as sentinels against ascending bacteria but also promote detrimental inflammation. The kidney medulla is characterized by extreme electrolyte...
Renal immune cells serve as sentinels against ascending bacteria but also promote detrimental inflammation. The kidney medulla is characterized by extreme electrolyte concentrations. We here address how its main osmolytes, NaCl and urea, regulate tubular cell cytokine expression and monocyte chemotaxis. In the healthy human kidney, more monocytes were detected in medulla than cortex. The monocyte gradient was attenuated in patients with medullary NaCl depletion by loop diuretic therapy and in the nephrotic syndrome. Renal tubular epithelial cell gene expression responded similarly to NaCl and tonicity control mannitol, but not urea. NaCl significantly upregulated chemotactic cytokines, most markedly CCL26, CCL2, and CSF1. This induction was inhibited by the ROS scavenger n-acetylcysteine. In contrast, urea, the main medullary osmolyte in catabolism, dampened tubular epithelial CCL26 and CSF1 expression. Renal medullary chemokine and monocyte marker expression decreased in catabolic mice. NaCl-, but not urea-stimulated tubular epithelium or CCL2 and CCL26, promoted human classical monocyte migration. CCL26 improved bactericidal function. In the human kidney medulla, monocyte densities correlated with tubular CCL26 protein abundance. In summary, medullary-range NaCl, but not urea, promotes tubular cytokine expression and monocyte recruitment. This may contribute to the pyelonephritis vulnerability in catabolism but can possibly be harnessed against pathologic inflammation.
Topics: Animals; Cytokines; Epithelial Cells; Humans; Inflammation; Kidney Medulla; Mice; Monocytes; Sodium Chloride; Urea
PubMed: 35527392
DOI: 10.1002/eji.202149723 -
Seminars in Nephrology Nov 2019The kidneys receive approximately 20% of cardiac output and have a low fractional oxygen extraction. Quite paradoxically, however, the kidneys are highly susceptible to... (Review)
Review
The kidneys receive approximately 20% of cardiac output and have a low fractional oxygen extraction. Quite paradoxically, however, the kidneys are highly susceptible to ischemic injury (injury associated with inadequate blood supply), which is most evident in the renal medulla. The predominant proposal to explain this susceptibility has been a mismatch between oxygen supply and metabolic demand. It has been proposed that unlike the well-perfused renal cortex, the renal medulla normally operates just above the threshold for hypoxia and that further reductions in renal perfusion cause hypoxic injury in this metabolically active region. An alternative proposal is that the true cause of ischemic injury is not a simple mismatch between medullary metabolic demand and oxygen supply, but rather the susceptibility of the outer medulla to vascular congestion. The capillary plexus of the renal outer medullary region is especially prone to vascular congestion during periods of ischemia. It is the failure to restore the circulation to the outer medulla that mediates complete and prolonged ischemia to much of this region, leading to injury and tubular cell death. We suggest that greater emphasis on developing clinically useful methods to help prevent or reverse the congestion of the renal medullary vasculature may provide a means to reduce the incidence and cost of acute kidney injury.
Topics: Acute Kidney Injury; Animals; Humans; Ischemia; Kidney Cortex; Kidney Medulla; Oxygen Consumption; Prognosis; Regional Blood Flow; Renal Artery; Renal Circulation; Vasoconstriction
PubMed: 31836035
DOI: 10.1016/j.semnephrol.2019.10.002 -
Toxicologic Pathology Oct 2019Microminipigs have become an attractive animal model for toxicology and pharmacology studies and for human disease models, owing to their manageable size. Although there...
Microminipigs have become an attractive animal model for toxicology and pharmacology studies and for human disease models, owing to their manageable size. Although there are numerous reports of spontaneous age-related lesions in mice, rats, dogs, and monkeys, those in minipigs are scarce. In the present study, spontaneous age-related histopathological changes were investigated using 37 microminipigs (20 males and 17 females) that were 6 months to 10 years of age. Abnormal deposits of materials were evident in several animals from 6 years of age, and these deposits included amyloid in the renal medulla, thyroid gland, and adrenal gland, hyaline droplets in glomeruli, and fibrillar inclusions in neurons. Arterial sclerosing changes (intimal thickening, intimal proliferation, and medial mineralization) and proliferative lesions (hyperplasia of hepatocytes, follicular cells, Leydig cells, and uterine endometrial glands) were present at 4 years of age and beyond. Renal adenoma, uterine leiomyoma, and Leydig cell tumor were observed in several microminipigs. Moreover, glomerulosclerosis, renal interstitial fibrosis, thymic involution, and adrenocortical cell vacuolation were common in aging microminipigs. Since knowledge of age-related changes is helpful for pathologists, the basic information obtained in this study will be a useful reference for all future toxicity evaluations in microminipigs.
Topics: Aging; Animals; Female; Kidney; Liver; Male; Swine; Swine, Miniature; Thyroid Gland; Tunica Intima
PubMed: 31337280
DOI: 10.1177/0192623319861350 -
Biology of Sex Differences Sep 2020Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential...
BACKGROUND
Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na transport. Activation of these receptors inhibits epithelial Na channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y and P2Y receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y and P2Y) receptors regulating Na excretion compared to male and OVX rats.
METHODS
To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y and P2Y receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E, 0, 10, 100, and 1000 nM) to test whether E increases mRNA expression of P2Y and P2Y receptors.
RESULTS
Acute P2 inhibition attenuated urinary Na excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y and P2Y mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E dose-dependently upregulated P2Y and P2Y mRNA expression in mIMCD3.
CONCLUSION
These data suggest that ovary-intact females have enhanced P2Y and P2Y-dependent regulation of Na handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na handling in premenopausal females.
Topics: Animals; Cell Line; Dose-Response Relationship, Drug; Epithelial Sodium Channels; Estradiol; Female; Gene Expression Regulation; Kidney Medulla; Male; Natriuresis; Ovariectomy; Ovary; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Sex Factors; Suramin; Type C Phospholipases
PubMed: 32928299
DOI: 10.1186/s13293-020-00329-0 -
American Journal of Physiology. Renal... Feb 2020The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with... (Review)
Review
The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with different composition of the peritubular environment. The TAL plays a critical role in the control of NaCl, water, acid, and divalent cation homeostasis, as illustrated by the consequences of the various monogenic diseases that affect the TAL. It delivers tubular fluid to the distal convoluted tubule and thereby affects the function of the downstream tubular segments. The TAL is commonly considered as a whole. However, many structural and functional differences exist between its medullary and cortical parts. The present review summarizes the available data regarding the similarities and differences between the medullary and cortical parts of the TAL. Both subsegments reabsorb NaCl and have high Na-K-ATPase activity and negligible water permeability; however, they express distinct isoforms of the Na-K-2Cl cotransporter at the apical membrane. Ammonia and bicarbonate are mostly reabsorbed in the medullary TAL, whereas Ca and Mg are mostly reabsorbed in the cortical TAL. The peptidic hormone receptors controlling transport in the TAL are not homogeneously expressed along the cortical and medullary TAL. Besides this axial heterogeneity, structural and functional differences are also apparent between species, which underscores the link between properties and role of the TAL under various environments.
Topics: Adaptation, Physiological; Animals; Evolution, Molecular; Humans; Kidney Cortex; Kidney Medulla; Loop of Henle; Membrane Transport Proteins; Renal Reabsorption; Species Specificity; Water-Electrolyte Balance
PubMed: 31841389
DOI: 10.1152/ajprenal.00261.2019 -
Biology Feb 2023Acute kidney injury (AKI) can result from multiple factors. The main cause is reduced renal perfusion. Kidneys are susceptible to ischemia due to the anatomy of... (Review)
Review
Acute kidney injury (AKI) can result from multiple factors. The main cause is reduced renal perfusion. Kidneys are susceptible to ischemia due to the anatomy of microcirculation that wraps around the renal tubules-peritubular capillary (PTC) network. Cortical and medullary superficial tubules have a large share in transport and require the supply of oxygen for ATP production, while it is the cortex that receives almost 100% of the blood flowing through the kidneys and the medulla only accounts for 5-10% of it. This difference makes the tubules present in the superficial layer of the medulla very susceptible to ischemia. Impaired blood flow causes damage to the endothelium, with an increase in its prothrombotic and pro-adhesive properties. This causes congestion in the microcirculation of the renal medulla. The next stage is the migration of pericytes with the disintegration of these vessels. The phenomenon of destruction of small vessels is called peritubular rarefaction, attributed as the main cause of further irreversible changes in the damaged kidney leading to the development of chronic kidney disease. In this article, we will present the characteristic structure of renal microcirculation, its regulation, and the mechanism of damage in acute ischemia, and we will try to find methods of prevention with particular emphasis on the inhibition of the renin-angiotensin-aldosterone system.
PubMed: 36829602
DOI: 10.3390/biology12020327 -
Neurosurgical Focus Nov 2019Although there is a substantial amount of research on the neurological consequences of traumatic brain injury (TBI), there is a knowledge gap regarding the relationship... (Review)
Review
Although there is a substantial amount of research on the neurological consequences of traumatic brain injury (TBI), there is a knowledge gap regarding the relationship between TBI and the pathophysiology of organ system dysfunction and autonomic dysregulation. In particular, the mechanisms or incidences of renal or cardiac complications after TBI are mostly unknown. Autonomic dysfunction following TBI exacerbates secondary injury and may contribute to nonneurologial complications that prolong hospital length of stay. Gaining insights into the mechanisms of autonomic dysfunction can guide advancements in monitoring and treatment paradigms to improve acute survival and long-term prognosis of TBI patients. In this paper, the authors will review the literature on autonomic dysfunction after TBI and possible mechanisms of paroxysmal sympathetic hyperactivity. Specifically, they will discuss the link among the brain, heart, and kidneys and review data to direct future research on and interventions for TBI-induced autonomic dysfunction.
Topics: Autonomic Nervous System Diseases; Brain; Brain Injuries, Traumatic; Heart; Humans; Kidney
PubMed: 31675718
DOI: 10.3171/2019.8.FOCUS19517 -
Nitric Oxide : Biology and Chemistry Aug 2022Hypertension significantly contributes to overall morbidity and mortality worldwide, and animal models of hypertension provide important tools to verify the... (Review)
Review
Hypertension significantly contributes to overall morbidity and mortality worldwide, and animal models of hypertension provide important tools to verify the physiological and molecular mechanisms underlying the development of the disease. A review of the most important models available would provide an insight into the appropriate targets to be addressed in the treatment of different forms of human hypertension. In the animal models discussed a special attention is given to the status and pathophysiological role of nitric oxide and its interaction with reactive oxygen species and oxidative stress. Another focus of the review are the processes running in the renal medulla which are still insufficiently explored. Deficient nitric oxide synthesis and its reduced bioavailability are important determinants of hypertension since NO is recognized as a major control factor of vascular tone homeostasis. For decades perfusion of the renal medulla has also been regarded as one of the blood pressure control factors and, noteworthily, the renal medulla belongs to the tissues with the highest NO content. The list of most often applied animal hypertension models reviewed here includes variants of salt-induced hypertension, the models with genetic background: such as spontaneously hypertensive rats (SHR) and Dahl salt sensitive (SS/SR) rats, Goldblatt 2K-1C hypertensive rats, and also the pharmacologically-plus-dietary salt-induced model known as DOCA-salt hypertension.
Topics: Animals; Blood Pressure; Humans; Hypertension; Models, Animal; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary
PubMed: 35700961
DOI: 10.1016/j.niox.2022.06.003 -
Nature Reviews. Nephrology Jun 2020Tonicity-responsive enhancer-binding protein (TonEBP), which is also known as nuclear factor of activated T cells 5 (NFAT5), was discovered 20 years ago as a... (Review)
Review
Tonicity-responsive enhancer-binding protein (TonEBP), which is also known as nuclear factor of activated T cells 5 (NFAT5), was discovered 20 years ago as a transcriptional regulator of the cellular response to hypertonic (hyperosmotic salinity) stress in the renal medulla. Numerous studies since then have revealed that TonEBP is a pleiotropic stress protein that is involved in a range of immunometabolic diseases. Some of the single-nucleotide polymorphisms (SNPs) in TONEBP introns are cis-expression quantitative trait loci that affect TONEBP transcription. These SNPs are associated with increased risk of type 2 diabetes mellitus, diabetic nephropathy, inflammation, high blood pressure and abnormal plasma osmolality, indicating that variation in TONEBP expression might contribute to these phenotypes. In addition, functional studies have shown that TonEBP is involved in the pathogenesis of rheumatoid arthritis, atherosclerosis, diabetic nephropathy, acute kidney injury, hyperlipidaemia and insulin resistance, autoimmune diseases (including type 1 diabetes mellitus and multiple sclerosis), salt-sensitive hypertension and hepatocellular carcinoma. These pathological activities of TonEBP are in contrast to the protective actions of TonEBP in response to hypertonicity, bacterial infection and DNA damage induced by genotoxins. An emerging theme is that TonEBP is a stress protein that mediates the cellular response to a range of pathological insults, including excess caloric intake, inflammation and oxidative stress.
Topics: Arthritis, Rheumatoid; Atherosclerosis; Autoimmune Diseases; Bacterial Infections; Carcinoma, Hepatocellular; DNA Damage; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Heat-Shock Proteins; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Liver Neoplasms; NFATC Transcription Factors; Obesity; Oxidative Stress; Polymorphism, Single Nucleotide; Salt Stress; Stress, Physiological; Virus Diseases
PubMed: 32157251
DOI: 10.1038/s41581-020-0261-1