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Kidney International Mar 2006Studies in patients with Bartter's and Gitelman's syndromes performed in the last 10 years have provided important insights into the mechanistic details of relevant... (Review)
Review
Studies in patients with Bartter's and Gitelman's syndromes performed in the last 10 years have provided important insights into the mechanistic details of relevant pathways of angiotensin II signaling and vascular tone regulation, therefore making these syndromes a good human model to gain insight into the mechanisms responsible for maintaining/controlling vascular tone. Extensive studies of patients with Bartter's/Gitelman's syndromes have, in fact, shown biochemical abnormalities of angiotensin II short- and long-term cell signaling, which depict a mirror image of those found in hypertension. The information obtained from the study of this human model of altered vascular tone regulation show that it can be used to gather more general data and/or confirm mechanistic details of the cellular and biochemical events involved in the pathophysiology of vascular tone control and to shed light on the multiplicity of the angiotensin II signaling-related mechanisms responsible for the pathophysiology of hypertension and its long-term complication such as cardiovascular remodeling and atherogenesis.
Topics: Angiotensin II; Bartter Syndrome; Blood Pressure; Blood Vessels; Calcium; Cardiovascular System; Endothelium, Vascular; GTP-Binding Proteins; Humans; Hypertension; Hypertrophy; Juxtaglomerular Apparatus; Magnesium; Oxidative Stress; Signal Transduction; Syndrome
PubMed: 16528244
DOI: 10.1038/sj.ki.5000253 -
Kidney Research and Clinical Practice Jun 2014Reninoma is a tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia because of hypersecretion of renin. We present a case of a...
Reninoma is a tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia because of hypersecretion of renin. We present a case of a 29-year-old female patient with reninoma and concomitant variant angina. The patient had uncontrolled hypertension and elevated plasma renin activity and aldosterone levels. Imaging studies revealed a mass in the left kidney, which was further confirmed as a renin-producing lesion via selective venous catheterization. During the evaluation, the patient had acute-onset chest pain that was diagnosed as variant angina after a provocation test. After partial nephrectomy, the plasma renin activity and plasma aldosterone levels decreased and blood pressure normalized. We report a case of reninoma with variant angina.
PubMed: 26877959
DOI: 10.1016/j.krcp.2014.03.001 -
Hypertension (Dallas, Tex. : 1979) Jul 2019In patients with diabetic kidney disease (DKD), plasma renin activity is usually decreased, but there is limited information on urinary renin and its origin. Urinary... (Comparative Study)
Comparative Study
In patients with diabetic kidney disease (DKD), plasma renin activity is usually decreased, but there is limited information on urinary renin and its origin. Urinary renin was evaluated in samples from patients with longstanding type I diabetes mellitus and mice with streptozotocin-induced diabetes mellitus. Renin-reporter mouse model (Ren1d-Cre;mT/mG) was made diabetic with streptozotocin to examine whether the distribution of cells of the renin lineage was altered in a chronic diabetic environment. Active renin was increased in urine samples from patients with DKD (n=36), compared with those without DKD (n=38; 3.2 versus 1.3 pg/mg creatinine; P<0.001). In mice with streptozotocin-induced diabetes mellitus, urine renin was also increased compared with nondiabetic controls. By immunohistochemistry, in mice with streptozotocin-induced diabetes mellitus, juxtaglomerular apparatus and proximal tubular renin staining were reduced, whereas collecting tubule staining, by contrast, was increased. To examine the role of filtration and tubular reabsorption on urinary renin, mice were either infused with either mouse or human recombinant renin and lysine (a blocker of proximal tubular protein reabsorption). Infusion of either form of renin together with lysine markedly increased urinary renin such that it was no longer different between nondiabetic and diabetic mice. Megalin mRNA was reduced in the kidney cortex of streptozotocin-treated mice (0.70±0.09 versus 1.01±0.04 in controls, P=0.01) consistent with impaired tubular reabsorption. In Ren1d-Cre;mT/mG with streptozotocin-induced diabetes mellitus, the distribution of renin lineage cells within the kidney was similar to nondiabetic renin-reporter mice. No evidence for migration of cells of renin linage to the collecting duct in diabetic mice could be found. Renin mRNA in microdissected collecting ducts from streptozotocin-treated mice, moreover, was not significantly different than in controls, whereas in kidney cortex, largely reflecting juxtaglomerular apparatus renin, it was significantly reduced. In conclusion, in urine from patients with type 1 diabetes mellitus and DKD and from mice with streptozotocin-induced diabetes mellitus, renin is elevated. This cannot be attributed to production from cells of the renin lineage migrating to the collecting duct in a chronic hyperglycemic environment. Rather, the elevated levels of urinary renin found in DKD are best attributed to altered glomerular filteration and impaired proximal tubular reabsorption.
Topics: Animals; Biopsy, Needle; Cohort Studies; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Models, Animal; Female; Glomerular Filtration Rate; Humans; Immunohistochemistry; Kidney Tubules, Collecting; Low Density Lipoprotein Receptor-Related Protein-2; Male; Mice; Mice, Transgenic; RNA, Messenger; Random Allocation; Reference Values; Renin; Sensitivity and Specificity; Urinalysis
PubMed: 31079532
DOI: 10.1161/HYPERTENSIONAHA.119.12873 -
Clinical and Experimental Nephrology Feb 2012Control of the renin system by physiological mechanisms such as the baroreceptor or the macula densa (MD) is characterized by asymmetry in that the capacity for renin... (Review)
Review
Control of the renin system by physiological mechanisms such as the baroreceptor or the macula densa (MD) is characterized by asymmetry in that the capacity for renin secretion and expression to increase is much larger than the magnitude of the inhibitory response. The large stimulatory reserve of the renin-angiotensin system may be one of the causes for the remarkable salt-conserving power of the mammalian kidney. Physiological stimulation of renin secretion and expression relies on the activation of regulatory pathways that converge on the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. Mice with selective Gs-alpha (Gsα) deficiency in juxtaglomerular granular cells show a marked reduction of basal renin secretion, and an almost complete unresponsiveness of renin release to furosemide, hydralazine, or isoproterenol. Cyclooxygenase-2 generating prostaglandin E(2) (PGE(2)) and prostacyclin (PGI(2)) in MD and thick ascending limb cells is one of the main effector systems utilizing Gsα-coupled receptors to stimulate the renin-angiotensin system. In addition, β-adrenergic receptors are critical for the expression of high basal levels of renin and for its release response to lowering blood pressure or MD sodium chloride concentration. Nitric oxide generated by nitric oxide synthases in the MD and in endothelial cells enhances cAMP-dependent signaling by stabilizing cAMP through cyclic guanosine monophosphate-dependent inhibition of phosphodiesterase 3. The stimulation of renin secretion by drugs that inhibit angiotensin II formation or action results from the convergent activation of cAMP probably through indirect augmentation of the activity of PGE(2) and PGI(2) receptors, β-adrenergic receptors, and nitric oxide.
Topics: Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 2; Diuretics; Furosemide; GTP-Binding Protein alpha Subunits, Gs; Juxtaglomerular Apparatus; Kidney Tubules, Distal; Mice; Nitric Oxide Synthase; Prostaglandins; Receptors, Adrenergic, beta; Renin; Renin-Angiotensin System; Signal Transduction
PubMed: 22124804
DOI: 10.1007/s10157-011-0494-1 -
Nephrology, Dialysis, Transplantation :... Oct 2008
Review
Topics: Animals; Diabetes Mellitus; Glucose; Humans; Juxtaglomerular Apparatus; Models, Biological; Nephrons; Paracrine Communication; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Succinic Acid
PubMed: 18644796
DOI: 10.1093/ndt/gfn377 -
Physiological Reports Sep 2021Olfactory receptor 78 (Olfr78) is a G protein-coupled receptor (GPCR) that is expressed in the juxtaglomerular apparatus (JGA) of the kidney as well as the peripheral...
Olfactory receptor 78 (Olfr78) is a G protein-coupled receptor (GPCR) that is expressed in the juxtaglomerular apparatus (JGA) of the kidney as well as the peripheral vasculature, and is activated by gut microbial metabolites. We previously reported that Olfr78 plays a role in renin secretion in isolated glomeruli, and that Olfr78 knockout (KO) mice have lower plasma renin activity. We also noted that in anesthetized mice, Olfr78KO appeared to be hypotensive. In this study, we used radiotelemetry to determine the role of Olfr78 in chronic blood pressure regulation. We found that the blood pressure of Olfr78KO mice is not significantly different than that of their WT counterparts at baseline, or on high- or low-salt diets. However, Olfr78KO mice have depressed heart rates on high-salt diets. We also report that Olfr78KO mice have lower renin protein levels associated with glomeruli. Finally, we developed a mouse where Olfr78 was selectively knocked out in the JGA, which phenocopied the lower renin association findings. In sum, these experiments suggest that Olfr78 modulates renin, but does not play an active role in blood pressure regulation at baseline, and is more likely activated by high levels of short chain fatty acids or hypotensive events. This study provides important context to our knowledge of Olfr78 in BP regulation.
Topics: Animals; Blood Pressure; Female; Hypertension; Kidney; Male; Mice; Mice, Inbred C57BL; Receptors, Odorant; Renin
PubMed: 34549531
DOI: 10.14814/phy2.15017 -
American Journal of Physiology. Renal... Jul 2003The molecular mechanisms with which the juxtaglomerular apparatus accomplishes its twin functions, acute regulation of glomerular blood flow and secretion of renin, are...
The molecular mechanisms with which the juxtaglomerular apparatus accomplishes its twin functions, acute regulation of glomerular blood flow and secretion of renin, are still not clearly understood. Least understood is the role of the extraglomerular mesangial (EM) cells, also known as lacis or Goormaghtigh cells, which lie sandwiched between the macula densa and the afferent and efferent arterioles. Here, we report that immunoreactivity for phospholemman (FXYD1), a single-span membrane protein homologous to the gamma (gamma) sub-unit of the Na,K-ATPase, is found in the kidney in EM cells with the Na,K-ATPase beta2-subunit and in cortical blood vessels and the afferent arteriole with Na,K-ATPase alpha2 and beta2. Phospholemman's distribution in EM cells is distinct from that of the Na,K-ATPase gamma-subunit, which is found on the basolateral surface of macula densa cells with Na,K-ATPase alpha1 and beta1. Phospholemman is a major kinase target, and its location in the juxtaglomerular apparatus suggests that it is involved in tubuloglomerular feedback.
Topics: Animals; Arterioles; Gene Expression; Glomerular Mesangium; Humans; Juxtaglomerular Apparatus; Membrane Proteins; Phosphoproteins; Rats; Renal Circulation; Signal Transduction; Sodium-Potassium-Exchanging ATPase
PubMed: 12657562
DOI: 10.1152/ajprenal.00241.2002 -
Asian Journal of Surgery Oct 2022
Topics: Foot; Hand; Humans; Juxtaglomerular Apparatus; Lower Extremity; Upper Extremity
PubMed: 35466030
DOI: 10.1016/j.asjsur.2022.04.022 -
Journal of the American Society of... Oct 2021Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of...
BACKGROUND
Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease.
METHODS
We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus , micropuncture of renal tubules , clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice.
RESULTS
Macula densa NOS1β was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1β, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1β expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies.
CONCLUSIONS
Macula densa NOS1β plays a critical role in the control of renal hemodynamics and BP during pregnancy.
Topics: Animals; Arterial Pressure; Chlorocebus aethiops; Feedback, Physiological; Female; Glomerular Filtration Rate; Hypertension, Pregnancy-Induced; Isoenzymes; Kidney Glomerulus; Kidney Tubules, Distal; Mice; Mice, Knockout; Nitric Oxide Synthase Type I; Pregnancy; Renal Circulation; Up-Regulation; Uterus
PubMed: 34127535
DOI: 10.1681/ASN.2020070969 -
The Journal of Clinical Investigation Jun 2021Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and...
Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.
Topics: Activin Receptors, Type II; Activins; Animals; Cachexia; Disease Models, Animal; HEK293 Cells; Humans; Mice; Mice, Knockout; Muscle, Skeletal; Muscular Atrophy; Renal Insufficiency, Chronic; Wasting Syndrome
PubMed: 34060483
DOI: 10.1172/JCI135821