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Cells Jul 2020The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The... (Review)
Review
The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca levels including the control of parathyroid hormone release and regulation of the renal calcium handling. Calcium reabsorption in the distal nephron of the kidney is functionally coupled to sodium transport. Apart from Ca transport systems, CaSR signaling affects relevant distal Na-(K)-2Cl cotransporters, NKCC2 and NCC. NKCC2 and NCC are activated by a kinase cascade comprising with-no-lysine [K] kinases (WNKs) and two homologous Ste20-related kinases, SPAK and OSR1. Gain-of-function mutations within the WNK-SPAK/OSR1-NKCC2/NCC pathway lead to renal salt retention and hypertension, whereas loss-of-function mutations have been associated with salt-losing tubulopathies such as Bartter or Gitelman syndromes. A Bartter-like syndrome has been also described in patients carrying gain-of-function mutations in the CaSR gene. Recent work suggested that CaSR signals via the WNK-SPAK/OSR1 cascade to modulate salt reabsorption along the distal nephron. The review presented here summarizes the latest progress in understanding of functional interactions between CaSR and WNKs and their potential impact on the renal salt handling and blood pressure.
Topics: Animals; Humans; Kidney; Nephrons; Protein Serine-Threonine Kinases; Receptors, Calcium-Sensing; Signal Transduction
PubMed: 32659887
DOI: 10.3390/cells9071644 -
Nature Reviews. Nephrology Oct 2021The mammalian vascular system consists of two networks: the blood vascular system and the lymphatic vascular system. Throughout the body, the lymphatic system... (Review)
Review
The mammalian vascular system consists of two networks: the blood vascular system and the lymphatic vascular system. Throughout the body, the lymphatic system contributes to homeostatic mechanisms by draining extravasated interstitial fluid and facilitating the trafficking and activation of immune cells. In the kidney, lymphatic vessels exist mainly in the kidney cortex. In the medulla, the ascending vasa recta represent a hybrid lymphatic-like vessel that performs lymphatic-like roles in interstitial fluid reabsorption. Although the lymphatic network is mainly derived from the venous system, evidence supports the existence of lymphatic beds that are of non-venous origin. Following their development and maturation, lymphatic vessel density remains relatively stable; however, these vessels undergo dynamic functional changes to meet tissue demands. Additionally, new lymphatic growth, or lymphangiogenesis, can be induced by pathological conditions such as tissue injury, interstitial fluid overload, hyperglycaemia and inflammation. Lymphangiogenesis is also associated with conditions such as polycystic kidney disease, hypertension, ultrafiltration failure and transplant rejection. Although lymphangiogenesis has protective functions in clearing accumulated fluid and immune cells, the kidney lymphatics may also propagate an inflammatory feedback loop, exacerbating inflammation and fibrosis. Greater understanding of lymphatic biology, including the developmental origin and function of the lymphatics and their response to pathogenic stimuli, may aid the development of new therapeutic agents that target the lymphatic system.
Topics: Animals; Humans; Kidney; Kidney Diseases; Lymphatic System
PubMed: 34158633
DOI: 10.1038/s41581-021-00438-y -
Current Opinion in Endocrinology,... Apr 2022To critically appraise new insights into HDL structure and function in type 1 diabetes (T1DM) and type 2 diabetes (T2DM). (Review)
Review
PURPOSE OF REVIEW
To critically appraise new insights into HDL structure and function in type 1 diabetes (T1DM) and type 2 diabetes (T2DM).
RECENT FINDINGS
In young T1DM patients with early renal impairment and a high inflammatory score, both HDL antioxidative activity and endothelial vasodilatory function were impaired, revealing a critical link between HDL dysfunction, subclinical vascular damage, systemic inflammation and end organ damage. HDL may inhibit development of T2DM by attenuating endoplasmic reticulum (ER) stress and apoptotic loss of pancreatic β-cells, an effect due in part to ABC transporter-mediated efflux of specific oxysterols with downstream activation of the hedghehog signalling receptor, Smoothened. The apoM-sphingosine-1-phosphate complex is critical to HDL antidiabetic activity, encompassing protection against insulin resistance, promotion of insulin secretion, enhanced β-cell survival and inhibition of hepatic glucose production. Structure-function studies of HDL in hyperglycemic, dyslipidemic T2DM patients revealed both gain and loss of lipidomic and proteomic components. Such changes attenuated both the optimal protective effects of HDL on mitochondrial function and its capacity to inhibit endothelial cell apoptosis. Distinct structural components associated with individual HDL functions.
SUMMARY
Extensive evidence indicates that both the proteome and lipidome of HDL are altered in T1DM and T2DM, with impairment of multiple functions.
Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Lipoproteins, HDL; Proteomics
PubMed: 34980868
DOI: 10.1097/MED.0000000000000705 -
Reviews of Physiology, Biochemistry and... 2023The transient receptor potential (TRP) channels, classified into six (-A, -V, -P, -C, -M, -ML, -N and -Y) subfamilies, are important membrane sensors and mediators of... (Review)
Review
The transient receptor potential (TRP) channels, classified into six (-A, -V, -P, -C, -M, -ML, -N and -Y) subfamilies, are important membrane sensors and mediators of diverse stimuli including pH, light, mechano-force, temperature, pain, taste, and smell. The mammalian TRP superfamily of 28 members share similar membrane topology with six membrane-spanning helices (S1-S6) and cytosolic N-/C-terminus. Abnormal function or expression of TRP channels is associated with cancer, skeletal dysplasia, immunodeficiency, and cardiac, renal, and neuronal diseases. The majority of TRP members share common functional regulators such as phospholipid PIP2, 2-aminoethoxydiphenyl borate (2-APB), and cannabinoid, while other ligands are more specific, such as allyl isothiocyanate (TRPA1), vanilloids (TRPV1), menthol (TRPM8), ADP-ribose (TRPM2), and ML-SA1 (TRPML1). The mechanisms underlying the gating and regulation of TRP channels remain largely unclear. Recent advances in cryogenic electron microscopy provided structural insights into 19 different TRP channels which all revealed close proximity of the C-terminus with the N-terminus and intracellular S4-S5 linker. Further studies found that some highly conserved residues in these regions of TRPV, -P, -C and -M members mediate functionally critical intramolecular interactions (i.e., within one subunit) between these regions. This review provides an overview on (1) intramolecular interactions in TRP channels and their effect on channel function; (2) functional roles of interplays between PIP2 (and other ligands) and TRP intramolecular interactions; and (3) relevance of the ligand-induced modulation of intramolecular interaction to diseases.
Topics: Animals; Humans; Transient Receptor Potential Channels; Protein Structure, Secondary; Menthol; Temperature; TRPV Cation Channels; Mammals
PubMed: 35882668
DOI: 10.1007/112_2022_74 -
Experimental and Clinical Endocrinology... Aug 2021
Topics: Diabetic Nephropathies; Diagnosis, Differential; Diagnostic Techniques, Endocrine; Disease Progression; Endocrinology; Germany; Humans; Hypertension; Preventive Medicine; Renal Insufficiency
PubMed: 33395705
DOI: 10.1055/a-1284-6211 -
Frontiers in Physiology 2020The Barker hypothesis strongly supported the influence of fetal environment on the development of chronic diseases in later life. Multiple experimental and human studies... (Review)
Review
The Barker hypothesis strongly supported the influence of fetal environment on the development of chronic diseases in later life. Multiple experimental and human studies have identified that the deleterious effect of fetal programming commonly leads to alterations in renal development. The interplay between environmental insults and fetal genome can induce epigenetic changes and lead to alterations in the expression of renal phenotype. In this review, we have explored the renal development and its functions, while focusing on the epigenetic findings and functional aspects of the renin-angiotensin system and its components.
PubMed: 33101064
DOI: 10.3389/fphys.2020.586290 -
Frontiers in Medicine 2023Chemical modifications are a specific and efficient way to regulate the function of biological macromolecules. Among them, RNA molecules exhibit a variety of... (Review)
Review
Chemical modifications are a specific and efficient way to regulate the function of biological macromolecules. Among them, RNA molecules exhibit a variety of modifications that play important regulatory roles in various biological processes. More than 170 modifications have been identified in RNA molecules, among which the most common internal modifications include N6-methyladenine (mA), n1-methyladenosine (mA), 5-methylcytosine (mC), and 7-methylguanine nucleotide (mG). The most widely affected RNA modification is mA, whose writers, readers, and erasers all have regulatory effects on RNA localization, splicing, translation, and degradation. These functions, in turn, affect RNA functionality and disease development. RNA modifications, especially mA, play a unique role in renal cell carcinoma disease. In this manuscript, we will focus on the biological roles of m6A in renal diseases such as acute kidney injury, chronic kidney disease, lupus nephritis, diabetic kidney disease, and renal cancer.
PubMed: 37841018
DOI: 10.3389/fmed.2023.1247690 -
Urologic Oncology Apr 2023To evaluate whether significant loss in ipsilateral renal parenchymal volume (IRPV) and renal function occurs during active surveillance (AS) of renal oncocytoma (RO)...
INTRODUCTION AND OBJECTIVE
To evaluate whether significant loss in ipsilateral renal parenchymal volume (IRPV) and renal function occurs during active surveillance (AS) of renal oncocytoma (RO) patients.
METHODS
Renal function (estimated glomerular filtration rate, eGFR) dynamics were retrospectively analyzed in 32 consecutive biopsy-diagnosed RO patients managed with AS at a National Comprehensive Cancer Network institute. Three-dimensional kidney and tumor reconstructions were generated and IRPV was calculated using volumetry software (Myrian®) for all patients with manually estimated RO growth >+10 cm. GFR and IRPV were compared at AS initiation vs. the last follow-up using 2-sided paired t-tests. The correlation between change in IRPV and change in RO size or GFR was tested using a Spearman coefficient.
RESULTS
With median follow-up of 37 months, there was no significant change between initial vs. last eGFR (median 71.0 vs. 70.5 ml/min/1.73 m, P = 0.50; median change -3.0 ml/min/1.73 m). Among patients (n = 17) with RO growth >+10 cm during AS (median growth +28.6 cm, IQR +16.9- + 46.5 cm), IRPV generally remained stable (median change +0.5%, IQR -1.2%- + 1.2%), with only 2 cases surpassing 5% loss. No IRPV loss was detected among any patient within the top tertile of RO growth magnitude. RO growth magnitude did not correlate with loss of either IRPV (ρ = -0.30, P = 0.24) or eGFR (ρ = -0.16, P = 0.40), including among patient subsets with lower initial eGFR. Study limitations include a lack of long-term follow-up.
CONCLUSIONS
Volumetry is a promising novel tool to measure kidney and tumor tissue changes during AS. Our study using volumetry indicates that clinically significant loss of IRPV or eGFR is uncommon and unrelated to tumor growth among untreated RO patients with intermediate follow-up. These findings support that AS is in general functionally safe for RO patients, however longer study is needed to determine safety durability, particularly among uncommon ≥cT2 RO variants.
Topics: Humans; Retrospective Studies; Watchful Waiting; Kidney; Kidney Neoplasms; Glomerular Filtration Rate; Nephrectomy
PubMed: 36842877
DOI: 10.1016/j.urolonc.2023.01.006 -
Seminars in Nephrology Jul 2021The kidney is one of the target organs that may show health disorders as a result of obesity. Obesity-related glomerulopathy (ORG) is a kidney disease category based on... (Review)
Review
The kidney is one of the target organs that may show health disorders as a result of obesity. Obesity-related glomerulopathy (ORG) is a kidney disease category based on a biopsy diagnosis that may occur secondary to obesity. Detailed clinicopathologic observations of ORG have provided significant knowledge regarding obesity-associated renal complications. Glomerulomegaly with focal segmental glomerulosclerosis of perihilar locations is a typical renal histopathologic finding in ORG, which has long been considered to represent a state of single-nephron glomerular hyperfiltration. This hypothesis was recently confirmed in ORG patients by estimating single-nephron glomerular filtration rate using a combined image analysis and biopsy-based stereology. Overshooting in glomerulotubular and tubuloglomerular interactions may lead to glomerular hyperfiltration/hypertension, podocyte failure, tubular protein-traffic overload, and tubulointerstitial scarring, constituting a vicious cycle of a common pathway to the further loss of functioning nephrons and the progression of kidney functional impairment.
Topics: Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Glomerulus; Obesity; Podocytes
PubMed: 34715960
DOI: 10.1016/j.semnephrol.2021.06.002 -
Seminars in Nuclear Medicine Jul 2022Nuclear medicine offers several diagnostic scans for the evaluation of congenital and acquired conditions of the kidneys and urinary track in children. Tc-99m-MAG 3... (Review)
Review
Nuclear medicine offers several diagnostic scans for the evaluation of congenital and acquired conditions of the kidneys and urinary track in children. Tc-99m-MAG 3 diuretic renal scans are most commonly used in the evaluation and follow up of urinary track dilatations. They provide functional information on the differential renal function and on drainage quality which is allows distinction between obstructed and non-obstructed kidneys and the need for surgical correction vs conservative management in kidneys with impaired drainage. Standardized imaging and processing protocols are essential for correct interpretation and for meaningful comparisons between follow up scans. Different approaches and conceptions led to some contradicting recommendations between SNMMI and EANM guidelines on diuretic renography in children which caused confusion and to the emergence of self-made institutional protocols. In Late 2018 the two societies published joint procedural guidelines on diuretic renography in infants and children which hopefully will end the confusion. Tc-99m DMSA scans provide important information about the function of the renal cortex allowing detection of acute pyelonephritis, renal scars dysplasia and ectopy as well as accurate determination of the differential renal function. They are commonly used in the evaluation of children with urinary tract infections and affect clinical management. A standardized imaging and processing protocol improves the diagnostic accuracy of these studies. SPECT or pinhole images should be a routine part of the imaging protocol. This is one of the recommendations in the new EANM and SNMMI procedural guidelines for renal cortical scintigraphy in children available online on the SNMMI website and is under publication. This article provides an overview on the clinical role of diuretic renography and cortical scintigraphy in children and describes the imaging protocols focusing on the new recommendations in the procedural guidelines.
Topics: Child; Diuretics; Humans; Kidney; Radioisotope Renography; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Dimercaptosuccinic Acid; Tomography, Emission-Computed, Single-Photon; Urology
PubMed: 35031115
DOI: 10.1053/j.semnuclmed.2021.12.002