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Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts.

Vasoactive endothelin (ET) is generated by ET converting enzyme (ECE)-induced proteolytic processing of pro-molecule big ET to biologically active peptides. H2O2 has been shown to increase the expression of ECE1 via transactivation of its promoter. The present study demonstrates that H2O2 triggered ECE1-dependent ET1-3 production in neonatal pig proximal tubule (PT) epithelial cells. A uniaxial stretch of PT cells decreased catalase, increased NADPH oxidase (NOX)2 and NOX4, and increased H2O2 levels. Stretch also increased cellular ECE1, an effect reversed by EUK-134 (a synthetic superoxide dismutase/catalase mimetic), NOX inhibitor apocynin, and siRNA-mediated knockdown of NOX2 and NOX4. Short-term unilateral ureteral obstruction (UUO), an inducer of renal tubular cell stretch and oxidative stress, increased renal ET1-3 generation and vascular resistance (RVR) in neonatal pigs. Despite removing the obstruction, UUO-induced increase in RVR persisted, resulting in early acute kidney injury (AKI). ET receptor (ETR)-operated Ca2+ entry in renal microvascular smooth muscle (SM) via transient receptor potential channel 3 (TRPC3) channels reduced renal blood flow and increased RVR. Although acute reversible UUO (rUUO) did not change protein expression levels of ETR and TRPC3 in renal microvessels, inhibition of ECE1, ETR, and TRPC3 protected against renal hypoperfusion, RVR increase, and early AKI. These data suggest that mechanical stretch-driven oxyradical generation stimulates ET production in neonatal pig renal epithelial cells. ET activates renal microvascular SM TRPC3, leading to persistent vasoconstriction and reduction in renal blood flow. These mechanisms may underlie rUUO-induced renal insufficiency in infants.

Members of the transient receptor potential (TRP) channels that are expressed in the kidney have gained prominence in recent years following discoveries of their role in maintaining the integrity of the filtration barrier, regulating tubular reabsorption of Ca2+ and Mg2+, and sensing osmotic stimuli. Furthermore, evidence has linked mutations in TRP channels to kidney disease pathophysiological mechanisms, including focal segmental glomerulosclerosis, disturbances in Mg2+ homeostasis, and polycystic kidney disease. Several subtypes of TRP channels are expressed in the renal vasculature, from preglomerular arteries and arterioles to the descending vasa recta. Although investigations on the physiological and pathological significance of renal vascular TRP channels are sparse, studies on isolated vessels and cells have suggested their involvement in renal vasoregulation. Renal blood flow (RBF) is an essential determinant of kidney function, including glomerular filtration, water and solute reabsorption, and waste product excretion. Functional alterations in ion channels that are expressed in the endothelium and smooth muscle of renal vessels can modulate renal vascular resistance, arterial pressure, and RBF. Hence, renal vascular TRP channels are potential therapeutic targets for the treatment of kidney disease. This review summarizes the current knowledge of TRP channel expression in renal vasculature and their role in controlling kidney function in health and disease.

To celebrate 100 years of American Heart Association-supported cardiovascular disease research, this review article highlights milestone papers that have significantly contributed to the current understanding of the signaling mechanisms driving hypertension and associated cardiovascular disorders. This article also includes a few of the future research directions arising from these critical findings. To accomplish this important mission, 4 principal investigators gathered their efforts to cover distinct yet intricately related areas of signaling mechanisms pertaining to the pathogenesis of hypertension. The renin-angiotensin system, canonical and novel contractile and vasodilatory pathways in the resistance vasculature, vascular smooth muscle regulation by membrane channels, and noncanonical regulation of blood pressure and vascular function will be described and discussed as major subjects. [ABSTRACT FROM AUTHOR]

Introduction: Cleistanthus collinus (C. collinus), a well known plant toxin, contains active principles like Cleistanthin A, Cleistanthin B, Cleistanthin C and Diphyllin. Previous human case reports and animal studies have revealed that C. collinus poisoning leads to type I Distal renal tubular acidosis and type II respiratory failure. However, the mechanism of toxicity of this plant is still uncertain. Based on the hypothesis that blockade of proton channels could result in type II respiratory failure, patch clamp experiments were done to see if Cleistanthin A blocked the proton channels. Aim: To record and compare the changes in the magnitude of voltage-gated proton currents in human neutrophils, before and after addition of Cleistanthin A (test) and control solution. Materials and Methods: The test compound Cleistanthin A was isolated by partition chromatography and characterised using thin layer chromatography. Neutrophils were isolated by density gradient centrifugation method. Using voltage clamp protocol, proton currents were recorded before (pre-intervention currents) and after (post-intervention currents) the addition of Cleistanthin A or control solution. The pre and post-intervention current densities for different voltages were compared within the groups (control and test) by Wilcoxon signed-rank test and the percentage current remaining in both the groups were compared using Mann-Whitney U test, p

The human eye is often discussed as optically equivalent to a photographic camera. The iris is compared with the shutter, the pupil to the aperture, and the retina to the film, and both have lens systems to focus rays of light. Although many similarities exist, a major difference between the two systems is the mechanism involved in focusing an object. In a camera, the focal length of each lens is fixed, and changes in focus are brought about by movement of the lenses. However, in the human eye, changes in focus are brought about by changes in the power of the lens by varying its curvature. Functional models of the eye are commercially available. Current prices of such models range from $400 upward. This article describes a simple and inexpensive model to illustrate the change in curvature of the human lens during accommodation.

Numerous models have been constructed to aid teaching respiratory mechanics. A simple model using a syringe and a water-filled bottle has been described by Thomas Sherman to explain inspiration and expiration. The elastic recoil of the chest wall and lungs has been described using a coat hanger or by using rods and rubber bands. A more complex two-component model has also been described by Kuebler et al. The model described in this article is a modification of the classical balloon and jar experiment that is simple to constructand explains the balance of forces at functional residual capacity (FRC). The model also uses the elastic nature of the materials to represent the elastic nature of the lung and chest wall. (Contains 2 figures.)

Physiology teaching often comprises of a large percentage of didactic lectures. A 1-h didactic lecture is often much longer than the average attention span of most students. It is preferable to use different methods to decrease the possible monotony of the didactic lecture. This is even more important when the topic being discussed has a greater number of facts that require memorizing. In this article, we describe a simple activity that can be used to enliven didactic teaching of the gastrointestinal system. This involved baking a cake and looking in detail at the ingredients of the cake and the different physiological processes that take place in the body as a piece of cake courses through the gastrointestinal tract.

Background: Ascorbic acid (AA) is known to modulate lymphocyte function, but the mechanism of action is not clearly understood. As voltage-gated potassium currents play an important role in lymphocyte function, the effect of AA on voltage-gated potassium currents was studied. Methods: Peripheral blood mononuclear cells were cultured in the presence of increasing concentrations of AA (0, 0.125, 0.25, 0.5, and 1 mM). Potassium currents in resting lymphocytes were studied by whole cell patch clamp technique using a depolarizing protocol. Lymphocyte function was assessed by measuring interleukin-2 (IL-2) secretion after mitogenic stimulation by ELISA. Results: The mean current density of potassium currents recorded from cells cultured for 48 h in the presence of 0.125 mM AA was not significantly different from that of cells cultured in the absence of AA. There was about 50% inhibition of IL-2 secretion in cell cultures with 0.125 mM AA when compared to controls without AA. At higher concentrations of AA, the IL-2 secretion decreased further. Conclusions: The results of the study indicate that the inhibition of lymphocyte function by AA in vitro may not be due to inhibition of potassium currents in the concentration tested. [ABSTRACT FROM AUTHOR]

We explored the association of novel urinary biomarkers with albumin-creatinine ratio (ACR) in adults with sickle cell anaemia. Of 37 participants, 13 (35.2%) had persistent albuminuria (PA). Urinary levels of clusterin (p = 0.002), retinol-binding protein 4 (p = 0.008), alpha-1 microglobulin (p = 0.002) and angiotensinogen (p = 0.006) were significantly higher in participants with PA than in those without PA. Although univariate analysis showed significant associations between both alpha-1 microglobulin (p = 0.035) and angiotensinogen (p = 0.0021) with ACR, only angiotensinogen was associated with ACR in multivariable analysis (p = 0.04). Our results suggest that urinary angiotensinogen may identify sickle cell anaemia patients at risk for kidney disease., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT 1 -5-HT 7 ), with 5-HT 2 predominantly mediating renal vasoconstriction. Cyclooxygenase (COX) and smooth muscle intracellular Ca 2+ levels ([Ca 2+ ] i ) have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. In the present study, we demonstrate that 5-HT stimulated human TRPV4 transiently expressed in Chinese hamster ovary cells. 5-HT 2A is the predominant 5-HT 2 receptor subtype in freshly isolated neonatal pig renal microvascular smooth muscle cells (SMCs). HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in the SMCs. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca 2+ ] i and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transdermal measurement of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC and 5-HT 2 receptor antagonist ritanserin attenuated 5-HT effects on RBF, RVR, and GFR. Moreover, the serum and urinary COX-1 and COX-2 levels in 5-HT-treated piglets were unchanged compared with the control. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production., Competing Interests: Declaration of competing interest The authors report no conflict of interest. The data underlying this article will be shared on reasonable request to the corresponding author., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI., Competing Interests: None., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)

Vasoactive endothelin (ET) is generated by ET converting enzyme (ECE)-induced proteolytic processing of pro-molecule big ET to biologically active peptides. H 2 O 2 has been shown to increase the expression of ECE1 via transactivation of its promoter. The present study demonstrates that H 2 O 2 triggered ECE1-dependent ET1-3 production in neonatal pig proximal tubule (PT) epithelial cells. A uniaxial stretch of PT cells decreased catalase, increased NADPH oxidase (NOX)2 and NOX4, and increased H 2 O 2 levels. Stretch also increased cellular ECE1, an effect reversed by EUK-134 (a synthetic superoxide dismutase/catalase mimetic), NOX inhibitor apocynin, and siRNA-mediated knockdown of NOX2 and NOX4. Short-term unilateral ureteral obstruction (UUO), an inducer of renal tubular cell stretch and oxidative stress, increased renal ET1-3 generation and vascular resistance (RVR) in neonatal pigs. Despite removing the obstruction, UUO-induced increase in RVR persisted, resulting in early acute kidney injury (AKI). ET receptor (ET R )-operated Ca 2+ entry in renal microvascular smooth muscle (SM) via transient receptor potential channel 3 (TRPC3) channels reduced renal blood flow and increased RVR. Although acute reversible UUO (rUUO) did not change protein expression levels of ET R and TRPC3 in renal microvessels, inhibition of ECE1, ET R , and TRPC3 protected against renal hypoperfusion, RVR increase, and early AKI. These data suggest that mechanical stretch-driven oxyradical generation stimulates ET production in neonatal pig renal epithelial cells. ET activates renal microvascular SM TRPC3, leading to persistent vasoconstriction and reduction in renal blood flow. These mechanisms may underlie rUUO-induced renal insufficiency in infants., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The expression levels of UII and UT in the kidney and circulating UII levels are increased in diabetes. UII also promotes mesangial proliferation and matrix accumulation in vitro. Here, we evaluate the effect of UT deletion on the development of hyperglycemia and diabetic kidney disease (DKD) in streptozotocin (STZ)-treated mice. Ten-week-old WT and UT knockout (KO) mice were injected with STZ for 5 days to induce diabetes. Blood glucose levels were measured weekly, and necropsy was performed 12 weeks after STZ injection. UT ablation slowed hyperglycemia and glucosuria in STZ-treated mice. UT KO also ameliorated STZ-induced increase in HbA1c, but not STZ-induced decrease in plasma insulin levels. However, STZ-induced increases in plasma glucagon concentration and immunohistochemical staining for glucagon in pancreatic islets were lessened in UT KO mice. UT ablation also protected against STZ-induced kidney derangements, including albuminuria, mesangial expansion, glomerular lesions, and glomerular endoplasmic reticulum stress. UT is expressed in a cultured pancreatic alpha cell line, and its activation by UII triggered membrane depolarization, T- and L-type voltage-gated Ca2+channel-dependent Ca2+influx, and glucagon secretion. These findings suggest that apart from direct action on the kidneys to cause injury, UT activation by UII may result in DKD by promoting hyperglycemia via induction of glucagon secretion by pancreatic alpha cells.

K V 7 channels, the voltage-gated K + channels encoded by KCNQ genes, mediate heterogeneous vascular responses in rodents. Postnatal changes in the functional expression of K V 7 channels have been reported in rodent saphenous arteries, but their physiological function in the neonatal renal vascular bed is unclear. Here, we report that, unlike adult pigs, only KCNQ1 (K V 7.1) out of the five members of KCNQ genes was detected in neonatal pig renal microvessels. KCNQ1 is present in fetal pig kidneys as early as day 50 of gestation, and the level of expression remains the same up to postnatal day 21 . Activation of renal vascular smooth muscle cell (SMC) K V 7.1 stimulated whole cell currents, inhibited by HMR1556 (HMR), a selective K V 7.1 blocker. HMR did not change the steady-state diameter of isolated renal microvessels. Similarly, intrarenal artery infusion of HMR did not alter mean arterial pressure, renal blood flow, and renal vascular resistance in the pigs. An ∼20 mmHg reduction in mean arterial pressure evoked effective autoregulation of renal blood flow, which HMR inhibited. We conclude that 1 ) the expression of KCNQ isoforms in porcine renal microvessels is dependent on kidney maturation, 2 ) K V 7.1 is functionally expressed in neonatal pig renal vascular SMCs, 3 ) a decrease in arterial pressure up to 20 mmHg induces renal autoregulation in neonatal pigs, and 4 ) SMC K V 7.1 does not control basal renal vascular tone but contributes to neonatal renal autoregulation triggered by a step decrease in arterial pressure. NEW & NOTEWORTHY K V 7.1 is present in fetal pig kidneys as early as day 50 of gestation, and the level of expression remains the same up to postnatal day 21 . K V 7.1 is functionally expressed in neonatal pig renal vascular smooth muscle cells (SMCs). A decrease in arterial pressure up to 20 mmHg induces renal autoregulation in neonatal pigs. Although SMC K V 7.1 does not control basal renal vascular resistance, its inhibition blunts neonatal renal autoregulation engendered by a step decrease in arterial pressure.

This sourcebook update describes a variation of a previous sourcebook experiment that used isolated extensor digitorum longus muscle from mouse to teach skeletal muscle properties (Head SI, Arber MS. Adv Physiol Educ 37: 405-414, 2013). Gastrocnemius-sciatic nerve preparation in an anaesthetized rat was developed and muscle contractions were recorded in a computerized data acquisition system using an isometric force transducer. Teachers and students in physiology or biology can use this preparation to demonstrate skeletal muscle properties like simple muscle twitch, quantal summation, wave summation, superposition, incomplete tetanus, complete tetanus, treppe, fatigue, and length-tension relationship.

Glomerular mesangial cell (GMC)-derived pleiotropic cytokine, interleukin-1 (IL-1), contributes to hypercellularity in human and experimental proliferative glomerulonephritis. IL-1 promotes mesangial proliferation and may stimulate extracellular matrix accumulation, mechanisms of which are unclear. The present study shows that the beta isoform of IL-1 (IL-1β) is a potent inducer of IL-1 type I receptor-dependent Ca 2+ entry in mouse GMCs. We also demonstrate that the transient receptor potential ankyrin 1 (TRPA1) is an intracellular store-independent diacylglycerol-sensitive Ca 2+ channel in the cells. IL-1β-induced Ca 2+ and Ba 2+ influxes in the cells were negated by pharmacological inhibition and siRNA-mediated knockdown of TRPA1 channels. IL-1β did not stimulate fibronectin production in cultured mouse GMCs and glomerular explants but promoted Ca 2+ -dependent cell proliferation. IL-1β also stimulated TRPA1-dependent ERK mitogen-activated protein kinase (MAPK) phosphorylation in the cells. Concomitantly, IL-1β-induced GMC proliferation was attenuated by TRPA1 and RAF1/ MEK/ERK inhibitors. These findings suggest that IL-1β-induced Ca 2+ entry via TRPA1 channels engenders MAPK-dependent mesangial cell proliferation. Hence, TRPA1-mediated Ca 2+ signaling could be of pathological significance in proliferative glomerulonephritis., (© 2021 Federation of American Societies for Experimental Biology.)

The Henderson-Hasselbalch equation can be considered as the backbone of acid base physiology. This is conventionally represented using two dimensional plots. Although two dimensional plots are simple to use, the equation in reality represents a surface in three dimensional space. Any combination of PaCO2, [HCO3 —] and blood pH values representing acid base disorders is restricted to this surface. Two models depicting the three dimensional surface generated by the Henderson-Hasselbalch equation were constructed from easily available materials. The first model was constructed using coloured beads, thin metal rods and plywood. This model depicted the Henderson-Hasselbalch surface as a collection of discreet points. The second model depicted the Henderson-Hasselbalch equation as a continuous surface using polystyrene sheets and white cement. The models were presented to undergraduate and post-graduate medical students along with other conventional two dimensional nomograms. Three dimensional models of the Henderson-Hasselbalch equation can serve as supplementary teaching material to ensure a deeper understanding of acid base physiology.

Voltage gated potassium channels present in T lymphocytes play an important role during lymphocyte activation. Though an increase in potassium currents has been reported in activated lymphocytes, changes in potassium currents in culture without activation by antigen or mitogen has not been reported. The peak potassium current densities on day 1 and day 5 of culture have been compared in this study. Peripheral blood mononuclear cells (PBMCs) were separated by density gradient centrifugation. Lymphocytes were separated from PBMCs by negative selection using anti-CD14 coated magnetic beads and cultured under appropriate conditions without antigenic or mitogenic stimulation. Lymphocytes were patched on day 1 or day 5 of culture. Voltage gated potassium currents were recorded by whole cell patch clamp technique using a depolarizing protocol. The mean of peak current densities recorded at +60 mV on day 1 of culture was 228.12 +/- 89.39 pA/pF (n = 7) and on day 5 of culture was 468.96 +/- 192.07 pA/pF (n = 7). The difference between the current densities on day 1 and day 5 was found to be significant. Change in electrophysiological characteristics can lead to functional changes in the lymphocytes and this should be considered when culturing lymphocytes in vitro for research and clinical use.

Background and Purpose: A water decoction of the poisonous shrub Cleistanthus collinus is used for suicidal purposes. The mortality rate is 28%. The clinical profile includes distal renal tubular acidosis (DRTA) and respiratory failure. The mechanism of toxicity is unclear., Objectives: To demonstrate features of C. collinus toxicity in a rat model and to identify its mechanism(s) of action., Materials and Methods: Rats were anesthetized and the carotid artery was cannulated. Electrocardiogram and respiratory movements were recorded. Either aqueous extract of C. collinus or control solution was administered intraperitoneally. Serial measurements of blood gases, electrolytes and urinary pH were made. Isolated brush border and basolateral membranes from rat kidney were incubated with C. collinus extract and reduction in ATPase activity was assessed. Venous blood samples from human volunteers and rats were incubated with an acetone extract of C. collinus and plasma potassium was estimated as an assay for sodium-potassium pump activity., Results: The mortality was 100% in tests and 17% in controls. Terminal event in test animals was respiratory arrest. Controls had metabolic acidosis, respiratory compensation acidic urine and hyperkalemia. Test animals showed respiratory acidosis, alkaline urine and low blood potassium as compared to controls. C. collinus extract inhibited ATPase activity in rat kidney. Plasma K(+) did not increase in human blood incubated with C. collinus extract., Conclusions and Implications: Active principles of C. collinus inhibit proton pumps in the renal brush border, resulting in type I DRTA in rats. There is no inhibition of sodium-potassium pump activity. Test animals develop respiratory acidosis, and the immediate cause of death is respiratory arrest.