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Cell Metabolism Mar 2024The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and animal models with chronic kidney disease, renal GCGR expression is reduced....
The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and animal models with chronic kidney disease, renal GCGR expression is reduced. However, the role of kidney GCGR in normal renal function and in disease development has not been addressed. Here, we examined its role by analyzing mice with constitutive or conditional kidney-specific loss of the Gcgr. Adult renal Gcgr knockout mice exhibit metabolic dysregulation and a functional impairment of the kidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucose output, oxidative stress, enhanced inflammasome activity, and excess lipid accumulation in the kidney. Upon a lipid challenge, they display maladaptive responses with acute hypertriglyceridemia and chronic proinflammatory and profibrotic activation. In aged mice, kidney Gcgr ablation elicits widespread renal deposition of collagen and fibronectin, indicative of fibrosis. Taken together, our findings demonstrate an essential role of the renal GCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficient for kidney Gcgr recapitulate some of the key pathophysiological features of chronic kidney disease.
Topics: Humans; Animals; Mice; Receptors, Glucagon; Down-Regulation; Mice, Knockout; Kidney; Renal Insufficiency, Chronic; Homeostasis; Lipids
PubMed: 38237602
DOI: 10.1016/j.cmet.2023.12.024 -
American Journal of Kidney Diseases :... Jan 2023The safety and efficacy of long-term exercise training in reducing physical functional loss in older adults with advanced CKD and comorbidity is uncertain. (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE & OBJECTIVE
The safety and efficacy of long-term exercise training in reducing physical functional loss in older adults with advanced CKD and comorbidity is uncertain.
STUDY DESIGN
Multicenter, parallel group, randomized controlled trial.
SETTINGS & PARTICIPANTS
Adults 55 years and older with estimated glomerular filtration rate (eGFR) of 15 to <45 mL/min/1.73 m enrolled from centers in Baltimore and Boston.
INTERVENTION
Twelve months of in-center supervised exercise training incorporating majority aerobic but also muscle strengthening activities or a group health education control intervention, randomly assigned in 1:1 ratio.
OUTCOME
Primary outcomes were cardiorespiratory fitness and submaximal gait at 6 and 12 months quantified by peak oxygen consumption (Vopeak) on graded exercise treadmill test and distance walked on the 6-minute walk test, respectively. Secondary outcomes were changes in lower extremity function, eGFR, albuminuria, glycemia, blood pressure, and body mass index.
RESULTS
Among 99 participants, the mean age was 68 years, 62% were African American, and the mean eGFR was 33 mL/min/1.73 m; 59% had diabetes, and 29% had coronary artery disease. Among those randomized to exercise, 59% of exercise sessions were attended in the initial 6 months. Exercise was well tolerated without excess occurrence of adverse events. At 6 months, aerobic capacity was higher among exercise participants (17.9 ± 5.5 vs 15.9 ± 7.0 mL/kg/min, P = 0.03), but the differences were not sustained at 12 months. The 6-minute walk distance improved more in the exercise group (adjusted difference: 98 feet [P = 0.02; P = 0.03 for treatment-by-time interaction]). The exercise group had greater improvements on the Timed Up and Go Test (P = 0.04) but not the Short Physical Performance Battery (P = 0.8).
LIMITATIONS
Planned sample size was not reached. Loss to follow-up and dropout were greater than anticipated.
CONCLUSIONS
Among adults aged ≥55 years with CKD stages 3b-4 and a high level of medical comorbidity, a 12-month program of in-center aerobic and resistance exercise training was safe and associated with improvements in physical functioning.
FUNDING
Government grants (National Institutes of Health).
TRIAL REGISTRATION
Registered at ClinicalTrials.gov with study number NCT01462097.
Topics: Humans; Aged; Postural Balance; Time and Motion Studies; Exercise; Physical Functional Performance; Renal Insufficiency, Chronic; Exercise Therapy
PubMed: 35944747
DOI: 10.1053/j.ajkd.2022.06.008 -
Frontiers in Endocrinology 2022
Topics: Endocrine System; Endocrinology
PubMed: 36204106
DOI: 10.3389/fendo.2022.1003683 -
Pflugers Archiv : European Journal of... Aug 2022Our kidneys receive about one-fifth of the cardiac output at rest and have a low oxygen extraction ratio, but may sustain, under some conditions, hypoxic injuries that... (Review)
Review
Our kidneys receive about one-fifth of the cardiac output at rest and have a low oxygen extraction ratio, but may sustain, under some conditions, hypoxic injuries that might lead to chronic kidney disease. This is due to large regional variations in renal blood flow and oxygenation, which are the prerequisite for some and the consequence of other kidney functions. The concurrent operation of these functions is reliant on a multitude of neuro-hormonal signaling cascades and feedback loops that also include the regulation of renal blood flow and tissue oxygenation. Starting with open questions on regulatory processes and disease mechanisms, we review herein the literature on renal blood flow and oxygenation. We assess the current understanding of renal blood flow regulation, reasons for disparities in oxygen delivery and consumption, and the consequences of disbalance between O delivery, consumption, and removal. We further consider methods for measuring and computing blood velocity, flow rate, oxygen partial pressure, and related parameters and point out how limitations of these methods constitute important hurdles in this area of research. We conclude that to obtain an integrated understanding of the relation between renal function and renal blood flow and oxygenation, combined experimental and computational modeling studies will be needed.
Topics: Humans; Hypoxia; Kidney; Oxygen; Oxygen Consumption; Renal Circulation
PubMed: 35438336
DOI: 10.1007/s00424-022-02690-y -
Clinical Neurophysiology : Official... Feb 2021Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of... (Review)
Review
Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.
Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.
Topics: Autonomic Nervous System; Consensus Development Conferences as Topic; Electrodiagnosis; Humans; Neurology; Neurophysiology; Practice Guidelines as Topic; Societies, Medical; Societies, Scientific
PubMed: 33419664
DOI: 10.1016/j.clinph.2020.11.024 -
Current Opinion in Nephrology and... Sep 2019Uromodulin (UMOD), also known as Tamm-Horsfall protein, is the most abundant protein in human urine. UMOD has multiple functions such as protection against urinary tract... (Review)
Review
PURPOSE OF REVIEW
Uromodulin (UMOD), also known as Tamm-Horsfall protein, is the most abundant protein in human urine. UMOD has multiple functions such as protection against urinary tract infections and nephrolithiasis. This review outlines recent progress made in UMOD's role in renal physiology, tubular transport, and mineral metabolism.
RECENT FINDINGS
UMOD is mostly secreted in the thick ascending limb (TAL) and to a lesser degree in the distal convoluted tubule (DCT). UMOD secretion is regulated by the calcium-sensing receptor. UMOD upregulates ion channels [e.g., renal outer medullary potassium channel, transient receptor potential cation channel subfamily V member 5, and transient receptor potential melastatin 6 (TRPM6)] and cotransporters [e.g., Na,K,2Cl cotransporter (NKCC2) and sodium-chloride cotransporter (NCC)] in the TAL and DCT. Higher serum UMOD concentrations have been associated with higher renal function and preserved renal reserve. Higher serum UMOD has also been linked to a lower risk of cardiovascular disease and diabetes mellitus.
SUMMARY
With better serum UMOD detection assays the extent of different functions for UMOD is still expanding. Urinary UMOD regulates different tubular ion channels and cotransporters. Variations of urinary UMOD secretion can so contribute to common disorders such as hypertension or nephrolithiasis.
Topics: Animals; Calcium; Humans; Hypertension; Ion Transport; Kidney Tubules; Magnesium; Minerals; Renal Insufficiency, Chronic; Uromodulin
PubMed: 31205055
DOI: 10.1097/MNH.0000000000000522 -
Diseases (Basel, Switzerland) Sep 2021Melatonin functions as a central regulator of cell and organismal function as well as a neurohormone involved in several processes, e.g., the regulation of the circadian... (Review)
Review
Melatonin functions as a central regulator of cell and organismal function as well as a neurohormone involved in several processes, e.g., the regulation of the circadian rhythm, sleep, aging, oxidative response, and more. As such, it holds immense pharmacological potential. Receptor-mediated melatonin function mainly occurs through MT1 and MT2, conserved amongst mammals. Other melatonin-binding proteins exist. Non-receptor-mediated activities involve regulating the mitochondrial function and antioxidant cascade, which are frequently affected by normal aging as well as disease. Several pathologies display diseased or dysfunctional mitochondria, suggesting melatonin may be used therapeutically. models have extensively been employed to study disease pathogenesis and discover new drugs. Here, we review the multiple functions of melatonin through the lens of functional conservation and model organism research to empower potential melatonin therapeutics to treat neurodegenerative and renal diseases.
PubMed: 34698120
DOI: 10.3390/diseases9040067 -
Medicina Clinica Aug 2021Individuals over 65years are the fastest expanding population throughout the world, due to the increase in human life expectancy. This growing geriatric population, with... (Review)
Review
Individuals over 65years are the fastest expanding population throughout the world, due to the increase in human life expectancy. This growing geriatric population, with increasingly associated chronic diseases, has relevant medical, social, and economic impact. Aging is characterized by progressive structural and functional changes in the kidney and in the cardiovascular system, leading to decline in renal function and hypertension. The purpose of this review is to describe the aging-related renal changes and blood pressure regulation during the aging process, their impact with regards to morbidity and mortality in these patients, and to summarize the most appropriate therapeutic approaches in these situations based on the particularities of this population group.
Topics: Aged; Aging; Humans; Hypertension; Kidney; Life Expectancy; Renal Insufficiency, Chronic
PubMed: 33858674
DOI: 10.1016/j.medcli.2021.02.008 -
Annual Review of Physiology Feb 2021Uromodulin, a protein exclusively produced by the kidney, is the most abundant urinary protein in physiological conditions. Already described several decades ago,... (Review)
Review
Uromodulin, a protein exclusively produced by the kidney, is the most abundant urinary protein in physiological conditions. Already described several decades ago, uromodulin has gained the spotlight in recent years, since the discovery that mutations in its encoding gene cause a renal Mendelian disease (autosomal dominant tubulointerstitial kidney disease) and that common polymorphisms are associated with multifactorial disorders, such as chronic kidney disease, hypertension, and cardiovascular diseases. Moreover, variations in uromodulin levels in urine and/or blood reflect kidney functioning mass and are of prognostic value for renal function, cardiovascular events, and overall mortality. The clinical relevance of uromodulin reflects its multifunctional nature, playing a role in renal ion transport and immunomodulation, in protection against urinary tract infections and renal stones, and possibly as a systemic antioxidant. Here, we discuss the multifaceted roles of this protein in kidney physiology and its translational relevance.
Topics: Animals; Cardiovascular Diseases; Humans; Hypertension; Kidney; Kidney Calculi; Renal Insufficiency, Chronic; Urinary Tract Infections; Uromodulin
PubMed: 33566673
DOI: 10.1146/annurev-physiol-031620-092817 -
Pflugers Archiv : European Journal of... Dec 2019Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in... (Review)
Review
Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in endothelial cell membrane of the renal medulla and in other tissues, including the brain, heart, pancreas, colon, bladder, bone marrow, and cochlea. UT-B is responsible for the maintenance of urea concentration, male reproductive function, blood pressure, bone metabolism, and brain astrocyte and cardiac functions. Its deficiency and dysfunction contribute to the pathogenesis of many diseases. Actually, UT-B deficiency increases the sensitivity of bladder epithelial cells to apoptosis triggers in mice and UT-B-null mice develop II-III atrioventricular block and depression. The expression of UT-B in the rumen of cow and sheep may participate in digestive function. However, there is no systemic review to discuss the UT-B functions. Here, we update research approaches to understanding the functions of UT-B.
Topics: Animals; Apoptosis; Epithelial Cells; Humans; Membrane Transport Proteins; Urea; Urinary Bladder; Urea Transporters
PubMed: 31734718
DOI: 10.1007/s00424-019-02323-x