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Human Pathology Oct 2022Juxtaglomerular cell tumors and glomus tumors both arise from perivascular mesenchymal cells. Juxtaglomerular cells are specialized renin-secreting myoendocrine cells in...
Juxtaglomerular cell tumors and glomus tumors both arise from perivascular mesenchymal cells. Juxtaglomerular cells are specialized renin-secreting myoendocrine cells in the afferent arterioles adjacent to glomeruli, and juxtaglomerular tumors derived from these cells are therefore unique to the kidney. In contrast, glomus tumors have been described at numerous anatomic sites and may show significant morphologic and immunophenotypic overlap with juxtaglomerular tumors when occurring in the kidney. Although ultrastructural studies and immunohistochemistry for renin may distinguish these entities, these diagnostic modalities are often unavailable in routine clinical practice. Herein, we studied the clinicopathologic features of a large series of juxtaglomerular tumors (n = 15) and glomus tumors of the kidney (n = 9) to identify features helpful in their separation, including immunohistochemistry for smooth muscle actin (SMA), CD34, collagen IV, CD117, GATA3, synaptophysin, and renin. Markers such as SMA (juxtaglomerular tumors: 12/13, 92%; glomus tumors: 9/9, 100%), CD34 (juxtaglomerular tumors: 14/14, 100%; glomus tumors: 7/9, 78%), and collagen IV (juxtaglomerular tumors: 5/6, 83%; glomus tumors: 3/3, 100%) were not helpful in separating these entities. In contrast to prior reports, all juxtaglomerular tumors were CD117 negative (0/12, 0%), as were glomus tumors (0/5, 0%). Our results show that juxtaglomerular tumors have a younger age at presentation (median age: 27 years), female predilection, and frequently exhibit diffuse positivity for renin (10/10, 100%) and GATA3 (7/9, 78%), in contrast to glomus tumors (median age: 51 years; renin: 0/6, 0%; GATA3: 0/6, 0%). These findings may be helpful in distinguishing these tumors when they exhibit significant morphologic overlap.
Topics: Actins; Adenoma; Adult; Antigens, CD34; Collagen Type IV; Female; GATA3 Transcription Factor; Glomus Tumor; Humans; Juxtaglomerular Apparatus; Kidney; Kidney Neoplasms; Middle Aged; Renin; Synaptophysin
PubMed: 35926808
DOI: 10.1016/j.humpath.2022.07.016 -
Anatomy & Cell Biology Dec 2020Camillo Golgi was an extraordinary scientist whose contributions in the domain of neuroanatomy proved to be critical for emergence of neuroscience as a sovereign... (Review)
Review
Camillo Golgi was an extraordinary scientist whose contributions in the domain of neuroanatomy proved to be critical for emergence of neuroscience as a sovereign scientific discipline. Golgi's invention of the () was a watershed event as it allowed remarkable visualization of the organizational pattern of elements of nervous system among complex puzzle of close knit interconnections. Till this time thin filamentary extensions of neural cells (axon and dendrites) could not be visualized with available staining techniques because of their slender and transparent nature. However invention of and its subsequent application demystified the basic architecture of brain tissue which was now visible to the scholars in all its complexity in microscopic studies. Golgi is also credited with the discovery of two types of sensory receptors in muscle tendons: Golgi tendon organ and Golgi-Mazzoni corpuscles. Golgi was the first to be successful in staining myelin component of axon, which he used to discover the myelin annular apparatus. He identified the complete life cycle of Plasmodium (malarial parasite) in human erythrocytes. His research on histological details of human kidney highlighted the existence of juxtaglomerular apparatus. Later on Spanish scientist Santiago Ramón y Cajal, based on the use of Golgi's Staining (Black Reaction) documented the morphologic details of nervous system in a more refined manner, which eventually led to the emergence of . In recognition of their exemplary contributions in neuroscience Golgi and Cajal were jointly awarded the Nobel Prize for Physiology or Medicine in 1906.
PubMed: 33012727
DOI: 10.5115/acb.20.196 -
Nephron 2023Gitelman syndrome (GS) is a rare renal tubular salt-wasting disorder. Besides kidney electrolyte loss, proteinuria and renal dysfunction were also observed. However,...
INTRODUCTION
Gitelman syndrome (GS) is a rare renal tubular salt-wasting disorder. Besides kidney electrolyte loss, proteinuria and renal dysfunction were also observed. However, their incidence, risk factors, pathological features, and prognosis were unclear.
METHODS
We retrospectively reviewed 116 GS patients and analyzed their clinical, genetic, and pathological characteristics. We also systematically reviewed articles on GS with proteinuria and renal dysfunction.
RESULTS
Twenty-three GS patients had proteinuria (69.6%) and renal dysfunction (43.5%) with a mean age of 35.3 ± 13.2 years, and 65.2% were male. Compared to patients without proteinuria or renal dysfunction, these patients had elevated plasma angiotensin II level (440.2 ± 351.7 vs. 253.2 ± 187.4 pg/mL, p = 0.031) and three times higher incidence of diabetes. The renal pathology of nine biopsied patients indicated hypertrophy of the juxtaglomerular apparatus (100%), chronic tubulointerstitial changes (66.7%), intrarenal vascular changes (66.7%), and glomerulopathy (55.6%). More extensive renin staining was observed in patients with GS than in the control group with glomerular minor lesion (p < 0.001). During a median of 85 months (range, 11-205 months) of follow-up for 19 out of the 23 GS-renal patients, the renal function was generally stable, except one died of cancer and one developed end-stage renal disease because of concomitant membranous nephropathy and IgA nephropathy.
CONCLUSION
Proteinuria and renal dysfunction were more common than expected and might indicate glomerulopathy and vascular lesions besides a tubulointerstitial injury in GS. Renal function may maintain stable with effective therapy in most cases.
Topics: Humans; Male; Young Adult; Adult; Middle Aged; Female; Gitelman Syndrome; Retrospective Studies; Kidney; Proteinuria; Glomerulonephritis, IGA
PubMed: 36806220
DOI: 10.1159/000529775 -
Journal of Biomedical Science Feb 2023Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein...
BACKGROUND
Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown.
METHODS
To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model.
RESULTS
In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion.
CONCLUSIONS
RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.
Topics: Animals; Humans; Mice; Aldosterone; Aluminum Oxide; Blood Pressure; Genome-Wide Association Study; Homeostasis; Hyperkalemia; Hypertension; Hypoaldosteronism; Potassium; Renin; Carrier Proteins
PubMed: 36803854
DOI: 10.1186/s12929-023-00905-7 -
The Journal of Physiology Apr 2024Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and...
Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin-1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero-Cre (P0-Cre) to abrogate Nrp1 constitutively in P0-Cre lineage-labelled cells of the kidney. We found that the P0-Cre precursor cells differentiate into renin-producing JG cells. We employed a lineage-tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell-autonomous role for NRP1 in JG cell function. Nrp1-deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0-Cre-expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. KEY POINTS: Renin is a centrepiece of the renin-angiotensin-aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin-1 (NRP1) is a conserved membrane-bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell-specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin-producing cells in the kidney and may open new avenues for therapeutic approaches.
Topics: Mice; Animals; Renin; Juxtaglomerular Apparatus; Neuropilin-1; Kidney; Mice, Knockout; Sodium
PubMed: 38381008
DOI: 10.1113/JP285422 -
Nature Reviews. Nephrology Jul 2024
Topics: Humans; Juxtaglomerular Apparatus; Animals
PubMed: 38816623
DOI: 10.1038/s41581-024-00853-x -
IScience Nov 2022Succinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is...
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is little evidence to guide systemic therapeutic options. We performed genomic profiling of a cohort of tumors through the analysis of whole genomes, transcriptomes, as well as flow cytometry and immunohistochemistry in order to gain a deeper understanding of their molecular biology. We find neutral evolution after early tumor activation with a lack of secondary driver events. We show that these tumors have epithelial derivation, possibly from the macula densa, a specialized paracrine cell of the renal juxtaglomerular apparatus. They subsequently develop into immune excluded tumors. We provide transcriptomic and protein expression evidence of a highly specific tumor marker, PAPPA2. These translational findings have implications for the diagnosis and treatment for this rare tumor subtype.
PubMed: 36345344
DOI: 10.1016/j.isci.2022.105389 -
Autopsy & Case Reports 2022Juxtaglomerular cell tumor is a benign, renin-secreting neoplasm. The tumor arises from the juxtaglomerular apparatus cells of the kidney. Because the tumor is...
Juxtaglomerular cell tumor is a benign, renin-secreting neoplasm. The tumor arises from the juxtaglomerular apparatus cells of the kidney. Because the tumor is hormonally active, patients usually suffer from hypokalemia, hyperaldosteronism, and hypertension. Herein, we describe a case of a 19-year-old Asian female with a somewhat unusual presentation. A 19-year-old Asian female presented with upper extremity weakness, numbness, and tingling. On physical examination, the only notable finding was hypertension. Extensive workup revealed elevated aldosterone level and plasma renin activity. CT scan of the abdomen revealed a 2.2 cm mass in the lower pole of the left kidney. The mass was resected by partial nephrectomy. On microscopic evaluation, the tumor had glomoid appearance with sheets of uniform, round to polygonal cells with clear to eosinophilic cytoplasm. Immunohistochemical stains showed the tumor cells to be positive for CD117, CD34 and CD10 and negative for ER, PR, CK7, PAX-8, pan-cytokeratin, EMA, S100, Melan-A, HMB45, SMA and CAIX. Diagnosis of Juxtaglomerular cell tumor was rendered. This case highlights the importance of a regular physical exam and a high index of suspicion in patients presenting with unusual complaints.
PubMed: 36312876
DOI: 10.4322/acr.2021.406 -
American Journal of Physiology. Renal... Dec 2021Macula densa (MD) cells, a chief sensory cell type in the nephron, are endowed with unique microanatomic features including a high density of protein synthetic...
Macula densa (MD) cells, a chief sensory cell type in the nephron, are endowed with unique microanatomic features including a high density of protein synthetic organelles and secretory vesicles in basal cell processes ("maculapodia") that suggest a so far unknown high rate of MD protein synthesis. This study aimed to explore the rate and regulation of MD protein synthesis and their effects on glomerular function using novel transgenic mouse models, newly established fluorescence cell biology techniques, and intravital microscopy. Sox2-tdTomato kidney tissue sections and an -propargyl puromycin incorporation-based fluorescence imaging assay showed that MD cells have the highest level of protein synthesis within the kidney cortex followed by intercalated cells and podocytes. Genetic gain of function of mammalian target of rapamycin (mTOR) signaling specifically in MD cells (in MD-mTOR mice) or their physiological activation by low-salt diet resulted in further significant increases in the synthesis of MD proteins. Specifically, these included both classic and recently identified MD-specific proteins such as cyclooxygenase 2, microsomal prostaglandin E synthase 1, and pappalysin 2. Intravital imaging of the kidney using multiphoton microscopy showed significant increases in afferent and efferent arteriole and glomerular capillary diameters and blood flow in MD-mTOR mice coupled with an elevated glomerular filtration rate. The presently identified high rate of MD protein synthesis that is regulated by mTOR signaling is a novel component of the physiological activation and glomerular hemodynamic regulatory functions of MD cells that remains to be fully characterized. This study discovered the high rate of protein synthesis in macula densa (MD) cells by applying direct imaging techniques with single cell resolution. Physiological activation and mammalian target of rapamycin signaling played important regulatory roles in this process. This new feature is a novel component of the tubuloglomerular cross talk and glomerular hemodynamic regulatory functions of MD cells. Future work is needed to elucidate the nature and (patho)physiological role of the specific proteins synthesized by MD cells.
Topics: Animals; Autocrine Communication; Diet, Sodium-Restricted; Glomerular Filtration Rate; Green Fluorescent Proteins; Humans; Intravital Microscopy; Juxtaglomerular Apparatus; Luminescent Proteins; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence, Multiphoton; Nitric Oxide Synthase Type I; Paracrine Communication; Protein Biosynthesis; Renin; Signal Transduction; Sodium, Dietary; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Red Fluorescent Protein; Mice
PubMed: 34693742
DOI: 10.1152/ajprenal.00222.2021 -
General and Comparative Endocrinology Sep 2020Renin or a renin-like enzyme evolved in ancestral vertebrates and is conserved along the vertebrate phylogeny. The ontogenic development of renin, however, is not well...
Renin or a renin-like enzyme evolved in ancestral vertebrates and is conserved along the vertebrate phylogeny. The ontogenic development of renin, however, is not well understood in nonmammalian vertebrates. We aimed to determine the expression patterns and relative abundance of renin mRNA in pre- and postnatal chickens (Gallus gallus, White Leghorn breed). Embryonic day 13 (E13) embryos show renal tubules, undifferentiated mesenchymal structures, and a small number of developing glomeruli. Maturing glomeruli are seen in post-hatch day 4 (D4) and day 30 (D30) kidneys, indicating that nephrogenic activity still exists in kidneys of 4-week-old chickens. In E13 embryos, renin mRNA measured by quantitative polymerase chain reaction in the adrenal glands is equivalent to the expression in the kidneys, whereas in post-hatch D4 and D30 maturing chicks, renal renin expressions increased 2-fold and 11-fold, respectively. In contrast, relative renin expression in the adrenals became lower than in the kidneys. Furthermore, renin expression is clearly visible by in situ hybridization in the juxtaglomerular (JG) area in D4 and D30 chicks, but not in E13 embryos. The results suggest that in chickens, renin evolved in both renal and extrarenal organs at an early stage of ontogeny and, with maturation, became localized to the JG area. Clear JG structures are not morphologically detectable in E13 embryos, but are visible in 30-day-old chicks, supporting this concept.
Topics: Animals; Chick Embryo; Chickens; Gene Expression Regulation; Juxtaglomerular Apparatus; Organogenesis; RNA, Messenger; Renin; Renin-Angiotensin System
PubMed: 32561435
DOI: 10.1016/j.ygcen.2020.113533