angiotensinogen and Carcinoma--Renal-Cell

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

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