angiotensinogen and Kidney-Neoplasms

In this review we describe the contributions made by immunocytochemistry to our knowledge of the renin-angiotensin system in the normal and the pathological kidney. Most of the renin-secreting cells appear to be on the outer aspect of the vessel wall, supporting the view that renin is secreted mainly into the interstitium of the kidney rather than into the lumen of the vessel. Angiotensin II immunoreactivity is present within renin-secreting cells. The angiotensin II appears to be present in high concentration in the renin storage granules and is therefore presumably secreted from the cell with renin. The pathways by which renin is secreted from the cell have also been clarified. In pathological kidneys, the reactions of renin-secreting cells to variation in functional demand have been confirmed. Renin-containing cells have also been found in most types of renal tumours and occasional cases probably secrete renin or prorenin into the blood. In renal tumours and in the developing kidney (in all species studied) the renin-containing cells are also intimately associated with blood vessels.

Topics: Angiotensinogen; Angiotensins; Animals; Autonomic Nervous System; Carcinoma, Renal Cell; Endopeptidases; Histocytochemistry; Humans; Immunochemistry; Infant; Juxtaglomerular Apparatus; Kidney; Kidney Glomerulus; Kidney Neoplasms; Kidney Tubules; Microvilli; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renal Circulation; Renin; Renin-Angiotensin System; Wilms Tumor

Enzymes, similar to kidney renin, are present in extrarenal tissue of most mammals; they hydrolyze angiotensinogen to form angiotensin I. We suggest that these enzymes be called angiotensinogenases. Angiotensinogenase concentrations in extrarenal tissue can exceed those in the kidney. The enzyme has been obtained in pure crystalline form. Angiotensinogenases are part of a complex enzyme system which leads to local production of angiotensin. Results indicating a biologic role of the angiotensinogenase system in brain, adrenal gland, uterus and tissue culture are discussed.

Topics: Adrenal Glands; Angiotensin II; Angiotensinogen; Animals; Brain; Cells, Cultured; Cerebrospinal Fluid; Female; Humans; Kidney Neoplasms; Mice; Rabbits; Rats; Renin; Submandibular Gland; Uterus

Patients with clear cell renal cell carcinoma (ccRCC) are often diagnosed with both von Hippel-Lindau (VHL) mutations and the constitutive activation of hypoxia-inducible factor-dependent signaling. In this study, we investigated the effects of long-term hypoxia in 786-O, a VHL-defective renal cell carcinoma cell line, to identify potential genes and microRNAs associated with tumor malignancy. The transcriptomic profiles of 786-O under normoxia, short-term hypoxia and long-term hypoxia were analyzed using next-generation sequencing. The results showed that long-term hypoxia promoted the ability of colony formation and transwell migration compared to normoxia. In addition, the differentially expressed genes induced by long-term hypoxia were involved in various biological processes including cell proliferation, the tumor necrosis factor signaling pathway, basal cell carcinoma and cancer pathways. The upregulated (

Topics: Adaptor Proteins, Signal Transducing; Angiotensinogen; Carcinoma, Renal Cell; Cell Cycle Proteins; Cell Hypoxia; Cell Line, Tumor; Cytoskeletal Proteins; Fibrillin-1; Humans; Kidney Neoplasms; MicroRNAs; Neural Cell Adhesion Molecule L1; Oxygen; Proteins; tau Proteins; Transcription Factors; Transcriptome

Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology.

Topics: Aged; Angiotensinogen; Carcinoma, Renal Cell; DNA, Neoplasm; Female; Follow-Up Studies; Gene-Environment Interaction; Humans; Hypertension; Kidney Neoplasms; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Potassium, Dietary; Prognosis; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sodium, Dietary

Hypertension is a known risk factor for renal cell carcinoma (RCC), although the underlying biological mechanisms of its action are unknown. To clarify the role of hypertension in RCC, we examined the risk of RCC in relation to 142 single-nucleotide polymorphisms (SNPs) in eight genes having a role in blood pressure control. We analyzed 777 incident and histologically confirmed RCC cases and 1035 controls who completed an in-person interview as part of a multi-center, hospital-based case-control study in Central Europe. Genotyping was conducted with an Illumina GoldenGate Oligo Pool All assay using germ line DNA. Of the eight genes examined, AGT (angiotensinogen) was most strongly associated with RCC (minimum P-value permutation test = 0.02). Of the 17 AGT tagging SNPs considered, associations were strongest for rs1326889 [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15-1.58] and rs2493137 (OR = 1.31, 95% CI = 1.12-1.54), which are located in the promoter. Stratified analysis revealed that the effects of the AGT SNPs were statistically significant in participants with hypertension or high body mass index (BMI) (> or =25 kg/m(2)), but not in subjects without hypertension and with a normal BMI (<25 kg/m(2)). Also, haplotypes with risk-conferring alleles of markers located in the promoter and intron 1 regions of AGT were significantly associated with RCC compared with the common haplotype in subjects with hypertension or high BMI (global P = 0.003). Our findings suggest that common genetic variants of AGT, particularly those in the promoter, increase RCC risk among subjects who are hypertensive or overweight.

Topics: Adult; Aged; Angiotensinogen; Body Mass Index; Carcinoma, Renal Cell; Case-Control Studies; Female; Haplotypes; Humans; Hypertension; Kidney Neoplasms; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Topics: Aged; Angiotensin II; Angiotensinogen; Captopril; Carcinoma, Renal Cell; Enzyme Precursors; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Pyelonephritis; Renal Dialysis; Renin; Renin-Angiotensin System

Renin biosynthesis was studied in a juxtaglomerular cell tumor. The tumoral tissue had a high renin content (180 Goldblatt Units/g of tissue), was heavily stained by immunofluorescence using human renin antiserum, and exhibited numerous characteristic secretory granules by electron microscopy. In one series of experiments, renin biosynthesis was studied in tissue slices, by following the incorporation of radiolabeled amino acids into specific immunoprecipitable renin. Time course studies showed that renin was first synthesized in a high molecular weight form, 55,000 mol wt, i.e., 10,000 mol wt higher than that of active renin, and was then converted into a 44,000-mol wt form. In a second series of experiments renin tumoral cells were cultured. Small, round, birefringent cells obtained after collagenase digestion produced renin in both primary culture and subculture media. After 5 d most of the renin found in the culture medium was inactive, but could be activated by trypsin treatment. The tumoral tissue exhibited a strong renin immunofluorescence and numerous secretory granules were observed by electron microscopy. In contrast, the renin-producing cells isolated from this tumor and grown in culture showed little renin immunofluorescence and no secretory granule could be observed. The renin-producing cells in primary culture and subculture were pulsed with radiolabeled amino acids, and immunoprecipitable radiolabeled renin was found in the culture media, thus demonstrating the actual biosynthesis of the enzyme. This renin was not stored inside cultured cells but was rapidly released into the medium and had a molecular weight of 55,000. No conversion of this inactive high molecular weight renin into the active, 44,000 mol wt form of renin was observed. We postulate the existence of two pathways for the processing, packaging, and secretion of renin in the tumoral cells: in juxtaglomerular cells of tumoral tissue renin is synthesized as a preprorenin and rapidly converted into prorenin (55,000 mol wt), which is in turn packaged in secretory granules where it is processed into active renin (44,000 mol wt) and finally secreted; in the cultured tumoral cells renin is still biosynthesized as a preprorenin molecule and then converted into prorenin, but is neither stored as granules nor processed into active renin. In this case the renin is released in an inactive form.

Topics: Adult; Angiotensinogen; Cell Transformation, Neoplastic; Cells, Cultured; Enzyme Activation; Enzyme Precursors; Humans; Juxtaglomerular Apparatus; Kidney Neoplasms; Male; Molecular Weight; Peptidyl-Dipeptidase A; Renin