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Annals of Plastic Surgery Dec 2022This study evaluated the potential of Wharton's jelly mesenchymal stem cells with high tolerogenic properties in reducing immunosuppressive dosage and related adverse...
BACKGROUND
This study evaluated the potential of Wharton's jelly mesenchymal stem cells with high tolerogenic properties in reducing immunosuppressive dosage and related adverse effects.
METHODS
A 4- to 6-week-old, 30-40 g weight, male inbred CD57BL/6 mice were used as skin allograft donors, whereas Balb/c mice with similar characteristics were used as recipients. Wharton's jelly stem cells were obtained from a commercial kit sourced from human umbilical cord. Skin allografts were performed from CD57Bl6 to Balb/c mice (day 0). Group 1 (control) received no treatment. Group 2 received 15 mg/kg cyclosporin A on days 0 to 30. Group 3 received 5.7 × 10 6 and 10.3 × 10 6 cell/kg Wharton's jelly stem cells on days 0 and 3, respectively. Groups 4, 5, and 6 received a combination of 15, 10, and 5 mg/kg per day cyclosporine A (days 0 to 30) with the same stem cell dose with group 3, respectively. Graft rejection was evaluated with digital photography and thermal imaging, histopathology (Banff grading, epithelialization scores, dermoepidermal dissociation), immunochemistry (Ki-67 and Bcl-2), and biochemical methods (interleukin 10, interleukin 2, interferon γ, tumor necrosis factor α) (day 10). Cumulative adverse effects of cyclosporin A occurring in the groups were revealed by histopathological evaluation of kidney and liver (a modified semiquantitative method of infiltration of inflammatory cells around the portal area and lobular region in liver; modification of the Banff rating of proximal tubules and hypertrophia of juxtaglomerular apparatus cells in kidney) (day 30).
RESULTS
There was no rejection in groups 2, 4, and 5 until the end of study. These were statistically different versus groups 1 (day 10 ± 0.71), 3 (day 11 ± 0.82), and 6 (day 11 ± 0.58) (all P 's < 0.05). Groups 4 and 5 have exhibited statistically similar findings in histopathological (4 epithelization score: 3.7 ± 1.3; 5 epithelization score: 3.5 ± 0.5; 4 Banff grading score: 0.8 ± 0.6; 5 Banff grading score: 1.0 ± 0.5; both P 's = 1.00), immunohistochemical (4 Bcl-2 score: 3.5 ± 0.5, P = 0.618; 5 Bcl-2 score: 3.4 ± 0.5, P = 1.00; 4 Ki-67 score: 3.7 ± 0.4, P = 1.00; 5 Ki-67 score: 3.5 ± 0.5, both P 's = 1.00), and levels of cytokines (both P 's = 1.00) versus group 2. Adverse effects on kidneys and liver were lowest and statistically similar in groups 3, 5, and 6 (all P 's = 00) versus group 1.
CONCLUSIONS
Wharton's jelly mesenchymal stem cells alter bioavailability of cyclosporine, albeit at much lower doses and with fewer systemic adverse effects.
Topics: Male; Humans; Mice; Animals; Cyclosporine; Ki-67 Antigen; Umbilical Cord; Mesenchymal Stem Cells; Mesoderm; Immunosuppressive Agents; Proto-Oncogene Proteins c-bcl-2
PubMed: 36416704
DOI: 10.1097/SAP.0000000000003314 -
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 -
International Journal of Molecular... Oct 2022In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na and water reabsorption in... (Review)
Review
In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na coupled with glucose and can restore renal O demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes.
Topics: Diabetes Mellitus; Diabetic Nephropathies; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36233288
DOI: 10.3390/ijms231911987 -
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 -
Pflugers Archiv : European Journal of... Aug 2022The protease renin, the key enzyme of the renin-angiotensin-aldosterone system, is mainly produced and secreted by juxtaglomerular cells in the kidney, which are located... (Review)
Review
The protease renin, the key enzyme of the renin-angiotensin-aldosterone system, is mainly produced and secreted by juxtaglomerular cells in the kidney, which are located in the walls of the afferent arterioles at their entrance into the glomeruli. When the body's demand for renin rises, the renin production capacity of the kidneys commonly increases by induction of renin expression in vascular smooth muscle cells and in extraglomerular mesangial cells. These cells undergo a reversible metaplastic cellular transformation in order to produce renin. Juxtaglomerular cells of the renin lineage have also been described to migrate into the glomerulus and differentiate into podocytes, epithelial cells or mesangial cells to restore damaged cells in states of glomerular disease. More recently, it could be shown that renin cells can also undergo an endocrine and metaplastic switch to erythropoietin-producing cells. This review aims to describe the high degree of plasticity of renin-producing cells of the kidneys and to analyze the underlying mechanisms.
Topics: Cell Differentiation; Juxtaglomerular Apparatus; Kidney; Kidney Glomerulus; Mesangial Cells; Myocytes, Smooth Muscle; Podocytes; Renin; Renin-Angiotensin System
PubMed: 35511367
DOI: 10.1007/s00424-022-02694-8 -
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 -
The Veterinary Clinics of North... Apr 2022Regulation of renal blood flow is by both extrinsic and intrinsic systems. Intrinsic regulation occurs via the afferent and efferent arterioles and tubuloglomerular... (Review)
Review
Regulation of renal blood flow is by both extrinsic and intrinsic systems. Intrinsic regulation occurs via the afferent and efferent arterioles and tubuloglomerular feedback mechanisms with activation of the juxtaglomerular apparatus. Mechanisms of acute kidney injury are frequently associated with changes in renal blood flow. Acute tubular necrosis and apoptosis are common in horses following ischemic or toxic insults and in sepsis-associated acute kidney injury. Sepsis-associated renal injury often has a complex mechanism of disease involving both functional and obstructive changes in intrarenal circulation. Acute interstitial nephritis may occur following Leptospira sp infection or can be secondary to tubular necrosis.
Topics: Acute Kidney Injury; Animals; Horse Diseases; Horses; Kidney; Nephritis, Interstitial; Renal Circulation
PubMed: 35282956
DOI: 10.1016/j.cveq.2021.11.001 -
Scientific Reports Mar 2022The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular...
The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular filtration and renin release. However, details of mechanosensory systems in these cells are unclear. Piezo2 is a recently identified mechanically activated ion channel found in various tissues, especially sensory neurons. Herein, we examined Piezo2 expression and regulation in mouse kidneys. RNAscope in situ hybridization revealed that Piezo2 expression was highly localized in mesangial cells and juxtaglomerular renin-producing cells. Immunofluorescence assays detected GFP signals in mesangial cells and juxtaglomerular renin-producing cells of Piezo2 reporter mice. Piezo2 transcripts were observed in the Foxd1-positive stromal progenitor cells of the metanephric mesenchyme in the developing mouse kidney, which are precursors of mesangial cells and renin-producing cells. In a mouse model of dehydration, Piezo2 expression was downregulated in mesangial cells and upregulated in juxtaglomerular renin-producing cells, along with the overproduction of renin and enlargement of the area of renin-producing cells. Furthermore, the expression of the renin coding gene Ren1 was reduced by Piezo2 knockdown in cultured juxtaglomerular As4.1 cells under static and stretched conditions. These data suggest pivotal roles for Piezo2 in the regulation of glomerular filtration and body fluid balance.
Topics: Animals; Ion Channels; Juxtaglomerular Apparatus; Kidney; Mesangial Cells; Mice; Renin
PubMed: 35273307
DOI: 10.1038/s41598-022-07987-7 -
Nutrients Feb 2022For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as... (Review)
Review
For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as the situation demands by the juxtaglomerular cells (also called as granular cells) that are in the walls of the afferent arterioles. Juxtaglomerular cells can sense minute changes in the blood pressure and blood volume and accordingly synthesize, store, and secrete appropriate amounts of renin. Thus, when the blood pressure and blood volume are decreased JGA cells synthesize and secrete higher amounts of renin and when the blood pressure and blood volume is increased the synthesis and secretion of renin is decreased such that homeostasis is restored. To decipher this important function, JGA cells (renin cells) need to sense and transmit the extracellular physical forces to their chromatin to control renin gene expression for appropriate renin synthesis. The changes in perfusion pressure are sensed by Integrin β1 that is transmitted to the renin cell's nucleus via lamin A/C that produces changes in the architecture of the chromatin. This results in an alteration (either increase or decrease) in renin gene expression. Cell membrane is situated in an unique location since all stimuli need to be transmitted to the cell nucleus and messages from the DNA to the cell external environment can be conveyed only through it. This implies that cell membrane structure and integrity is essential for all cellular functions. Cell membrane is composed to proteins and lipids. The lipid components of the cell membrane regulate its (cell membrane) fluidity and the way the messages are transmitted between the cell and its environment. Of all the lipids present in the membrane, arachidonic acid (AA) forms an important constituent. In response to pressure and other stimuli, cellular and nuclear shape changes occur that render nucleus to act as an elastic mechanotransducer that produces not only changes in cell shape but also in its dynamic behavior. Cell shape changes in response to external pressure(s) result(s) in the activation of cPLA2 (cytosolic phospholipase 2)-AA pathway that stretches to recruit myosin II which produces actin-myosin cytoskeleton contractility. Released AA can undergo peroxidation and peroxidized AA binds to DNA to regulate the expression of several genes. Alterations in the perfusion pressure in the afferent arterioles produces parallel changes in the renin cell membrane leading to changes in renin release. AA and its metabolic products regulate not only the release of renin but also changes in the vanilloid type 1 (TRPV1) expression in renal sensory nerves. Thus, AA and its metabolites function as intermediate/mediator molecules in transducing changes in perfusion and mechanical pressures that involves nuclear mechanotransduction mechanism. This mechanotransducer function of AA has relevance to the synthesis and release of insulin, neurotransmitters, and other soluble mediators release by specialized and non-specialized cells. Thus, AA plays a critical role in diseases such as diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, sepsis, lupus, rheumatoid arthritis, and cancer.
Topics: Arachidonic Acid; Juxtaglomerular Apparatus; Mechanotransduction, Cellular; Pressoreceptors; Renin
PubMed: 35215399
DOI: 10.3390/nu14040749