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American Journal of Physiology. Renal... Jun 2018Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and...
Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, and confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses, resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricemia.
Topics: Age Factors; Animals; Blood Pressure; Cation Transport Proteins; Disease Models, Animal; Diuretics; Genetic Predisposition to Disease; Hypertension; Hyperuricemia; Kidney; Kidney Diseases; Male; Membrane Microdomains; Mice, 129 Strain; Mice, Knockout; Monocarboxylic Acid Transporters; Oliguria; Organic Anion Transporters; Phenotype; Renin-Angiotensin System; Sodium-Hydrogen Exchanger 3; Solute Carrier Family 12, Member 1; Urination; Uromodulin
PubMed: 29357410
DOI: 10.1152/ajprenal.00233.2017 -
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 -
Kidney Medicine 2020Anorexia nervosa is often intractable and induces various physical disorders, including kidney disease and mineral disorders, occasionally progressing to kidney failure....
RATIONALE & OBJECTIVE
Anorexia nervosa is often intractable and induces various physical disorders, including kidney disease and mineral disorders, occasionally progressing to kidney failure. No consensus-based clinical practice guidelines have been established for patients with anorexia nervosa referred to a nephrologist.
STUDY DESIGN
Patients with anorexia nervosa-associated kidney disease diagnosed were analyzed retrospectively. Kidney outcomes were defined as doubling of serum creatinine level and/or progression to end-stage kidney disease.
SETTING & PARTICIPANTS
Patients with a history of anorexia nervosa with kidney disease, including electrolyte abnormalities, who were referred to our hospital between 1992 and 2017 were included.
RESULTS
14 female patients were included. The time from anorexia nervosa onset to the initial visit with a nephrologist was 17.8 years. At the first visit, median body mass index was 13.4 kg/m, median serum creatinine level was 1.9 mg/dL, and median serum potassium level was 2.7 mmol/L. All patients showed hypokalemia and addictive vomiting or diuretic/laxative abuse. During the median observation period of 3.1 years, kidney outcomes occurred in 9 patients, and 2 died due to their anorexia nervosa. 4 patients underwent kidney biopsy. The kidney biopsy findings of these patients included hypertrophy of the juxtaglomerular apparatus, advanced glomerular collapse, and interstitial fibrosis, consistent with ischemic kidney injury and hypokalemic nephropathy.
LIMITATIONS
The sample size was small, and kidney function was assessed based on serum creatinine levels in patients with anorexia nervosa with low muscle mass.
CONCLUSIONS
Most patients with anorexia nervosa referred to nephrologists had kidney disease at the time of the first visit. Improving kidney outcomes of patients with anorexia nervosa may require earlier collaboration between psychiatrists and nephrologists.
PubMed: 32775981
DOI: 10.1016/j.xkme.2020.03.007 -
Acta Medica Portuguesa May 2019Juxtaglomerular tumours are rare causes of secondary hypertension. They typically present with difficult-to-manage hypertension, hypokalemia, hyperreninemia and...
Juxtaglomerular tumours are rare causes of secondary hypertension. They typically present with difficult-to-manage hypertension, hypokalemia, hyperreninemia and secondary hyperaldosteronism. The authors describe a clinical case of a 45 years old female patient, with personal history of difficult-to-manage hypertension and hypokalemia since age 35, medicated with four types of anti-hypertensive agents. An analytical study was performed, which revealed secondary hyperaldosteronism [aldosterone 44.3 ng/dL (4 - 28 ng/dL), renin > 1000 mIU/mL (4.4 - 46.2 mIU/mL)]. Abdominal computed tomography scan identified a heterogeneous nodule located in the middle third of the right kidney, with 3.7 cm. Partial nephrectomy was performed and histological analysis confirmed the diagnosis of reninoma. After surgery, the patient had normal levels of aldosterone (9.2 ng/dL) and renin (1.20 mIU/mL), as well as normal blood pressure. The authors want to highlight this potentially curable cause of endocrine hypertension. Surgical resection is the treatment of choice and leads to normalization of blood pressure.
PubMed: 31738705
DOI: 10.20344/amp.11660 -
Korean Journal of Pediatrics Apr 2019The most common type of refractory hypertension found in children is secondary hypertension, which is a potentially curable disease. Reninoma, a renin-secreting...
The most common type of refractory hypertension found in children is secondary hypertension, which is a potentially curable disease. Reninoma, a renin-secreting juxtaglomerular cell tumor, is a rare cause of severe hypertension that is usually diagnosed in adolescents and young adults. Surgical resection of the tumor completely cures the hypertension of patients with reninoma. The typical clinical presentation of reninoma includes hypokalemia, metabolic alkalosis, and features secondary to the increased activation of the renin-angiotensin system without renal artery stenosis. We report a case of reninoma in a female adolescent with a typical clinical presentation, in which surgical removal of the tumor completely cured hypertension. We discuss here the clinical features, imaging studies, and immunohistochemical examination of the tumor used to establish the diagnosis of reninoma and for the management of the condition.
PubMed: 30376707
DOI: 10.3345/kjp.2018.06926 -
Iranian Journal of Kidney Diseases Oct 2017Embryogenesis of the kidney glomeruli, especially its vascular component, has not been well documented. Glomeruli capillary tuft is surrounded and enveloped by visceral...
INTRODUCTION
Embryogenesis of the kidney glomeruli, especially its vascular component, has not been well documented. Glomeruli capillary tuft is surrounded and enveloped by visceral epithelial cells, which is a unique portal system that connects afferent with efferent arteriole without interaction with venular circulation. We hypothesized that the portal system embryologically has developed by extension of the intima of afferent arteriole into the stroma of glomerulus. We also hypothesized that juxtaglomeruli apparatus was developed from remnants of smooth muscle cells of the media of afferent arteriole at the anastomosing site with the Bowman capsule entrance.
MATERIALS AND METHODS
We studied 5 human fetal kidneys by hematoxylin-eosin, periodic acid-Schiff, and immunoperoxidase staining techniques.
RESULTS
Hematoxylin-eosin staining of fetal kidney showed presence of erythrocytes in early vesicle form of glomeruli that was confirmed by immunohistochemical staining with CD31, smooth muscle actin, and CD34 markers. These stains showed extension of extraglomerular arterioles to the glomeruli. Periodic acid-Schiff staining showed also the continuity of the basement membrane in extraglomeruli and internal glomerular vascular tufts.
CONCLUSIONS
This study shows that there is a relationship between the metanephric blast cells and major vessel critical for angiogenesis. When afferent arteriole come in contact with the immature glomeruli, its intima migrates into the glomerular tuft to form intraglomerular capillary system, while its smooth muscle remains at the entrance orifice and develops juxtaglomerular apparatus cells.
Topics: Arterioles; Biomarkers; Embryonic Development; Fetal Development; Humans; Immunohistochemistry; Juxtaglomerular Apparatus
PubMed: 29038391
DOI: No ID Found -
Kidney International Mar 2022An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the...
An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of kidney tubules in vivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.
Topics: Animals; Diabetes Mellitus, Experimental; Feedback; Glomerular Filtration Rate; Kidney Glomerulus; Kidney Tubules; Mice; Nitric Oxide; Nitric Oxide Synthase Type I; Sodium-Glucose Transporter 1
PubMed: 34843754
DOI: 10.1016/j.kint.2021.10.037 -
Journal of the American Society of... Aug 2016Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, β-, and γ-splice...
Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, β-, and γ-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1β expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1β expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1β mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1α-knockout (NOS1αKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P<0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P<0.01) fed a high-salt diet. These results indicate that NOS1β is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.
Topics: Animals; Hypertension; Juxtaglomerular Apparatus; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type I; Sodium Chloride, Dietary
PubMed: 26647426
DOI: 10.1681/ASN.2015050515 -
International Journal of Surgical... Feb 2020Juxtaglomerular cell tumor (JGCT) is a rare renal tumor with a predominantly benign clinical course. It affects young adults, who often present with hypertension,... (Review)
Review
Juxtaglomerular cell tumor (JGCT) is a rare renal tumor with a predominantly benign clinical course. It affects young adults, who often present with hypertension, hypokalemia, and hyperaldosteronism. The tumor cells are round to spindle-shaped with occasional mild to moderate atypia, but mitotic figures are usually absent. Surgical resection is the treatment of choice. Typically, the blood pressure and renin levels normalize after removal of the tumor. Rare cases of metastatic and recurrent JGCT have been reported including cases with vascular invasion. These cases typically occur in older adults and present with larger tumor size (9-15 cm). We report a case of JGCT, 5.5 cm in greatest dimension, with atypical pathological features including invasion of the renal vein, lymphovascular invasion, and significant pleomorphism with rhabdoid morphology, along with a brief review of the literature.
Topics: Adult; Humans; Juxtaglomerular Apparatus; Kidney Neoplasms; Male; Neoplasm Invasiveness
PubMed: 31432719
DOI: 10.1177/1066896919868773 -
Archives of Virology Feb 2023There is an urgent need to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions involved in virus spread and pathogenesis, which...
There is an urgent need to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions involved in virus spread and pathogenesis, which might contribute to the identification of new therapeutic targets. In this study, we investigated the presence of SARS-CoV-2 in postmortem lung, kidney, and liver samples of patients who died with coronavirus disease (COVID-19) and its relationship with host factors involved in virus spread and pathogenesis, using microscopy-based methods. The cases analyzed showed advanced stages of diffuse acute alveolar damage and fibrosis. We identified the SARS-CoV-2 nucleocapsid (NC) in a variety of cells, colocalizing with mitochondrial proteins, lipid droplets (LDs), and key host proteins that have been implicated in inflammation, tissue repair, and the SARS-CoV-2 life cycle (vimentin, NLRP3, fibronectin, LC3B, DDX3X, and PPARγ), pointing to vimentin and LDs as platforms involved not only in the viral life cycle but also in inflammation and pathogenesis. SARS-CoV-2 isolated from a patient´s nasal swab was grown in cell culture and used to infect hamsters. Target cells identified in human tissue samples included lung epithelial and endothelial cells; lipogenic fibroblast-like cells (FLCs) showing features of lipofibroblasts such as activated PPARγ signaling and LDs; lung FLCs expressing fibronectin and vimentin and macrophages, both with evidence of NLRP3- and IL1β-induced responses; regulatory cells expressing immune-checkpoint proteins involved in lung repair responses and contributing to inflammatory responses in the lung; CD34 liver endothelial cells and hepatocytes expressing vimentin; renal interstitial cells; and the juxtaglomerular apparatus. This suggests that SARS-CoV-2 may directly interfere with critical lung, renal, and liver functions involved in COVID-19-pathogenesis.
Topics: Humans; COVID-19; Fibronectins; Vimentin; SARS-CoV-2; Endothelial Cells; NLR Family, Pyrin Domain-Containing 3 Protein; PPAR gamma; Lung; Inflammation; Kidney; Liver
PubMed: 36842152
DOI: 10.1007/s00705-023-05711-y