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Revista Da Associacao Medica Brasileira... Jan 2020Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for... (Review)
Review
Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.
Topics: Benzhydryl Compounds; Canagliflozin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glomerular Filtration Rate; Glucose; Glucosides; Humans; Hypoglycemic Agents; Kidney; Kidney Diseases; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 31939531
DOI: 10.1590/1806-9282.66.S1.17 -
Hypertension (Dallas, Tex. : 1979) Feb 2020Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as...
Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.
Topics: Aging; Animals; Blood Pressure; Disease Models, Animal; Glomerular Filtration Rate; Homeostasis; Hypertension; Kidney; Male; Mice; Mice, Inbred C57BL; Renal Circulation; Vasoconstriction
PubMed: 31838907
DOI: 10.1161/HYPERTENSIONAHA.119.13588 -
Frontiers in Pharmacology 2019Chronic kidney disease (CKD) is characterized by renal dysfunction, which is a common feature of other major diseases, such as hypertension and diabetes. Unilateral...
Chronic kidney disease (CKD) is characterized by renal dysfunction, which is a common feature of other major diseases, such as hypertension and diabetes. Unilateral ureteral obstruction (UUO) has been used as a model of CKD in experimental animals and consists of total obstruction of one kidney ureter. The UUO decreases renal blood flow, which promotes the synthesis of renin in the juxtaglomerular apparatus, the first step in renin-angiotensin system (RAS) cascade. RAS induces inflammation and remodeling, along with reduced renal function. However, it remains unknown whether intrarenal RAS (iRAS) is activated in early stages of CKD. Our objective was to characterize different iRAS components in the renal cortex and in the medulla in an early phase of UUO. Male C57BL/6 mice (8-12 weeks old) were subjected to UUO in the left kidney, or to sham surgery, and were euthanized after 7 days ( = 5/group). Renal function, renal inflammatory/remodeling processes, and iRAS expression were evaluated. UUO increased plasma creatinine, right renal hypertrophy (9.08 ± 0.31, < 0.05 vs. Sham), and tubular dilatation in the left kidney cortex (42.42 ± 8.19µm, < 0.05 vs. Sham). This correlated with the increased mRNA of IL-1β (1.73 ± 0.14, < 0.01 vs. Sham, a pro-inflammatory cytokine) and TGF-β1 (1.76 ± 0.10, < 0.001 vs. Sham, a pro-fibrotic marker). In the renal cortex of the left kidney, UUO increased the mRNA and protein levels of renin (in 35% and 28%, respectively, P < 0.05 vs. Sham). UUO decreased mRNA and protein levels for the (pro)renin receptor in the renal medulla (0.67 ± 0.036 and 0.88 ± 0.028, respectively, < 0.05 vs. Sham). Our results suggest that modulation of iRAS components depends on renal localization and occurs in parallel with remodeling and pro-inflammatory/pro-fibrotic mechanisms.
PubMed: 31803050
DOI: 10.3389/fphar.2019.01314 -
American Journal of Physiology. Renal... Feb 2020Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells that give rise to JG cells or a subset of smooth muscle cells of the...
Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells that give rise to JG cells or a subset of smooth muscle cells of the renal afferent arteriole. During periods of dehydration and salt deprivation, renal mesenchymal stromal cells (MSCs) differentiate from JG cells. JG cells undergo expansion and smooth muscle cells redifferentiate to express renin along the afferent arteriole. Gene expression profiling comparing resident renal MSCs with JG cells indicates that the transcription factor Sox6 is highly expressed in JG cells in the adult kidney. In vitro, loss of Sox6 expression reduces differentiation of renal MSCs to renin-producing cells. In vivo, Sox6 expression is upregulated after a low-Na diet and furosemide. Importantly, knockout of Sox6 in Ren1d+ cells halts the increase in renin-expressing cells normally seen during a low-Na diet and furosemide as well as the typical increase in renin. Furthermore, Sox6 ablation in renin-expressing cells halts the recruitment of smooth muscle cells along the afferent arteriole, which normally express renin under these conditions. These results support a previously undefined role for Sox6 in renin expression.
Topics: Animals; Arterioles; Blood Pressure; Cell Differentiation; Cell Proliferation; Cells, Cultured; Diet, Sodium-Restricted; Diuretics; Furosemide; Gene Expression Regulation; Juxtaglomerular Apparatus; Male; Mesenchymal Stem Cells; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Renin; SOXD Transcription Factors; Signal Transduction
PubMed: 31760770
DOI: 10.1152/ajprenal.00095.2019 -
Current Urology Sep 2019Juxtaglomerular cell tumor (JGCT), or reninoma, is a typically benign neoplasm generally affecting adolescents and young adults due to modified smooth muscle cells from... (Review)
Review
Juxtaglomerular cell tumor (JGCT), or reninoma, is a typically benign neoplasm generally affecting adolescents and young adults due to modified smooth muscle cells from the afferent arteriole of the juxtaglomerular apparatus. Patients experience symptoms related to hypertension and hypoka-lemia due to renin-secretion by the tumor. MRI, PET, CT, and renal vein catheterizations can be used to capture JGCTs, with laparoscopic ultrasonography being most cost-efective. Surgical removal is the best option for management; electrolyte imbalances are a potential complication which may be assuaged via pre-surgical administration of aliskiren, a renin inhibitor. Considering the vast etiology for hypertension and rarity of JGCT, the diagnosing physician must have a high index of suspicion for JGCT. Early recognition and management can help prevent cardiovascular or pregnancy complications and fatalities, vascular invasion and metastasis, improve quality of life, and limit socioeconomic liabilities. Herein we review the epidemiology, genetics, histopathol-ogy, clinical presentation, and management of this rare condition. The impact of genetics on prognosis warrant further research.
PubMed: 31579192
DOI: 10.1159/000499301 -
BMC Medical Genetics Aug 2019Bartter syndrome (BS) is a rare autosomal recessive disorder of salt reabsorption at the thick ascending limb of the Henle loop, characterized by hypokalemia, salt loss,...
BACKGROUND
Bartter syndrome (BS) is a rare autosomal recessive disorder of salt reabsorption at the thick ascending limb of the Henle loop, characterized by hypokalemia, salt loss, metabolic alkalosis, hyperreninemic hyperaldosteronism with normal blood pressure. BS type III, often known as classic BS (CBS), is caused by loss-of-function mutations in CLCNKB (chloride voltage-gated channel Kb) encoding basolateral ClC-Kb.
CASE PRESENTATION
We reported a 15-year-old CBS patient with a compound heterozygous mutation of CLCNKB gene. She first presented with vomiting, hypokalemic metabolic alkalosis at the age of 4 months, and was clinically diagnosed as CBS. Indomethacin, spironolactone and oral potassium were started from then. During follow-up, the serum electrolyte levels were generally normal, but the patient showed failure to thrive and growth hormone (GH) deficiency was diagnosed. The recombinant human GH therapy was performed, and the growth velocity was improved. When she was 14, severe proteinuria and chronic kidney disease (CKD) were developed. Renal biopsy showed focal segmental glomerulosclerosis (FSGS) with juxtaglomerular apparatus cell hyperplasia, and genetic testing revealed a point deletion of c.1696delG (p. Glu566fs) and a fragment deletion of exon 2-3 deletions in CLCNKB gene. Apart from the CBS, ostium secundum atrial septal defect (ASD) was diagnosed by echocardiography.
CONCLUSIONS
This is the first report of this compound heterozygous of CLCNKB gene in BS Children. Our findings contribute to a growing list of CLCNKB mutations associated with CBS. Some recessive mutations can induce CBS in combination with other mutations.
Topics: Adolescent; Asian People; Bartter Syndrome; Chloride Channels; Dwarfism, Pituitary; Female; Genetic Association Studies; Genetic Predisposition to Disease; Heart Septal Defects, Atrial; Heterozygote; Humans; Juxtaglomerular Apparatus; Mutation; Pedigree; Renal Insufficiency, Chronic
PubMed: 31409296
DOI: 10.1186/s12881-019-0869-9 -
Frontiers in Pharmacology 2019Pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) is, in combination with diuretics, the first-choice treatment for hypertension, although...
Pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) is, in combination with diuretics, the first-choice treatment for hypertension, although 10-20% of patients do not respond adequately. Next to the RAAS, the nitric oxide/cGMP/protein kinase G (PKG) system is the second fundamental blood pressure regulator. Whether both systems influence each other is not well-studied. It has been shown that nitric oxide (NO) supports renin recruitment activation of soluble guanylate cyclase (sGC) and subsequent generation of cGMP. Whether this leads to an ensuing activation of PKGs in this context is not known. PKGIα, as well as PKGII, is expressed in renin-producing cells. Hence, we analyzed whether these enzymes play a role regarding renin synthesis, secretion, or recruitment. We generated renin-cell-specific PKGI-knockout mice and either stimulated or inhibited the renin system in these mice by salt diets. To exclude the possibility that one kinase isoform can compensate the lack of the other, we also studied double-knockout animals with a conditional knockout of PKGI in juxtaglomerular cells (JG cells) and a ubiquitous knockout of PKGII. We analyzed blood pressure, renin mRNA and renal renin protein content as well as plasma renin concentration. Furthermore, we stimulated the cGMP system in these mice using BAY 41-8543, an sGC stimulator, and examined renin regulation either after acute administration or after 7 days (application once daily). We did not reveal any striking differences regarding long-term renin regulation in the studied mouse models. Yet, when we studied the acute effect of BAY 41-8543 on renin secretion in isolated perfused kidneys as well as in living animals, we found that the administration of the substance led to a significant increase in plasma renin concentration in control animals. This effect was completely abolished in double-knockout animals. However, after 7 days of once daily application, we did not detect a persistent increase in renin mRNA or protein in any studied genotype. Therefore, we conclude that in mice, cGMP and PKG are involved in the acute regulation of renin release but have no influence on long-term renin adjustment.
PubMed: 31379575
DOI: 10.3389/fphar.2019.00800 -
Laparoscopic partial nephrectomy for Juxtaglomerular apparatus tumour: A rare cause of hypertension.Urology Case Reports Sep 2019We report on the case of a partial nephrectomy for a Juxtaglomerular apparatus (JGA) tumour in a 28 year old female who presented with fatigue and symptomatic...
We report on the case of a partial nephrectomy for a Juxtaglomerular apparatus (JGA) tumour in a 28 year old female who presented with fatigue and symptomatic hypertension, and a normal serum renin level on pre-operative work-up.
PubMed: 31372343
DOI: 10.1016/j.eucr.2019.100910 -
Lupus Aug 2019The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies...
BACKGROUND
The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies could be adopted as a marker of treatment response and prognosis.
METHODS
Thirty renal biopsies from patients with LN were selected and analyzed through immunohistochemistry. Laboratory and clinical data were retrospectively collected at baseline, 6 and 12 months and at the latest clinical appointment. A number of patients (63.3%) were treated with rituximab (RTX) +/- methylprednisolone in the induction phase. The expression of HLA-G in glomeruli, tubules and infiltrating cells was examined and compared between lupus patients who achieved either complete or partial renal response and those who did not respond to treatment.
RESULTS
HLA-G staining was observed in the glomeruli of 20 of 30 samples from patients with LN. The expression of the antigen was detected in podocytes, along glomerular capillary walls, on parietal glomerular epithelial cells and within the juxtaglomerular apparatus. Seventy per cent of patients whose glomeruli expressed HLA-G achieved partial or complete response at 6 months and 75% at the latest available follow up compared with 30% and 40%, respectively, of those who did not show any expression. The pattern of staining in tubules and infiltrating cells was highly variable precluding any clinical correlation.
CONCLUSION
This study demonstrates that HLA-G is expressed in renal tissue in LN. Our retrospective data suggest that its expression could correlate with response to treatment.
Topics: Adult; Anti-Inflammatory Agents; Biopsy; Female; Follow-Up Studies; HLA-G Antigens; Humans; Immunologic Factors; Lupus Nephritis; Male; Methylprednisolone; Middle Aged; Pilot Projects; Retrospective Studies; Rituximab; Treatment Outcome; Young Adult
PubMed: 31291846
DOI: 10.1177/0961203319860582 -
American Journal of Physiology. Renal... Aug 2019As shown in our previous paper (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. 312: F1101-F1111, 2017), mesangial matrix expansion in diabetic...
As shown in our previous paper (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. 312: F1101-F1111, 2017), mesangial matrix expansion in diabetic nephropathy (DN) results for a major part from the accumulation of worn-out undegraded glomerular basement membrane material. Here, based on the reevaluation of >900 biopsies of DN, we show that this process continues with the progression of the disease finally leading to the herniation of the matrix-overloaded tuft through the glomerular entrance to the outside. This leads to severe changes in the glomerular surroundings, including a dissociation of the juxtaglomerular apparatus with displacement of the macula densa. The herniation is associated with a prominent outgrowth of glomerular vessels from the tuft. Mostly, these aberrant vessels are an abnormal type of arteriole with frequent intramural insudations of plasma. They spread into glomerular surroundings extending in intertubular and periglomerular spaces. Their formation is associated with elevated mRNA levels of vascular endothelial growth factor-A, angiopoietins 1 and 2, and the corresponding receptors. Functionally, these processes seem to compromise tubuloglomerular feedback-related functions and may be one factor why Na-glucose cotransporter-2 inhibitors are not effective in advanced stages of DN.
Topics: Angiopoietin-1; Angiopoietin-2; Arterioles; Diabetic Nephropathies; Disease Progression; Glomerular Mesangium; Humans; Juxtaglomerular Apparatus; Neovascularization, Pathologic; Receptor, TIE-2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 31141396
DOI: 10.1152/ajprenal.00617.2018