Renin synthesis and secretion by principal cells of the collecting duct (CD) is enhanced in angiotensin (Ang) II-dependent hypertension. The presence of renin/(pro)renin and its receptor, the (pro)renin receptor [(P)RR], in the CD may provide a pathway for Ang I generation with further conversion to Ang II. To assess if (P)RR activation occurs during Ang II-dependent hypertension, we examined renal (P)RR levels and soluble (P)RR (s(P)RR) excretion in the urine of chronic Ang II-infused rats (80 ng/min; for 2-weeks, n=10) and sham-operated rats (n=10). Systolic blood pressure and Ang II levels in the plasma and kidney were increased while plasma renin activity was suppressed in Ang II-infused rats. Renal (P)RR transcripts were upregulated in the cortex and medulla of Ang II-infused rats. (P)RR immunoreactivity in CD cells and the protein levels of the full-length form (37 kDa band) were significantly decreased in the medulla of Ang II-infused rats. The soluble (P)RR (28 kDa band) was detected in the renal medulla and urine samples of Ang II-infused rats which also showed increases in urinary renin content. To determine if the s(P)RR could stimulate Ang I formation, urine samples were incubated with recombinant human (pro)renin. Urine samples of Ang II-infused rats exhibited increased Ang I formation compared to sham-operated rats. Thus, in chronic Ang II-infused rats the catalytic activity of the augmented renin produced in the CD may be enhanced by the intraluminal s(P)RR and cell-surface located (P)RR, thus contributing to enhanced intratubular Ang II formation.
During renin-angiotensin system activation, cyclooxygenase-2 (COX-2)-derived prostaglandins attenuate the pressor and antinatriuretic effects of angiotensin II (AngII) in the renal medulla. The (pro)renin receptor (PRR) is abundantly expressed in the collecting ducts (CD) and its expression is augmented by AngII. PRR overexpression upregulates COX-2 via mitogen-activated kinases (MAPK/ERK1/2) in renal tissues; however, it is not clear if this effect occurs independently or in concert with AngII type 1 receptor (AT1R) activation. We hypothesized that PRR activation stimulates COX-2 expression independently of AT1R in primary cultures of rat renal inner medullary (IM) cells. The use of different cell-specific immunomarkers (aquaporin-2 for principal cells, anion exchanger type-1 for intercalated type-A cells, and tenascin C for interstitial cells) and co-staining for AT1R, COX-2 and PRR revealed that PRR and COX-2 were colocalized in intercalated and interstitial cells while principal cells did not express PRR or COX-2. In normal rat kidney sections, PRR and COX-2 were colocalized in intercalated and interstitial cells. In rat renal IM cultured cells, treatment with AngII (100 nmol/L) increased COX-2 expression via AT1R. In addition, AngII and rat recombinant prorenin (rrPR; 100 nmol/L) treatments increased ERK1/2 phosphorylation, independently. Importantly, rrPR upregulated COX-2 expression in the presence of AT1R blockade. Inhibition of MAPK/ERK1/2 suppressed COX-2 upregulation mediated by either AngII or rrPR. Furthermore, PRR knockdown using PRR-short hairpin RNA blunted the rrPR-mediated upregulation of COX-2. These results indicate that COX-2 expression is upregulated by activation of either PRR or AT1R via MAPK/ERK1/2 in rat renal IM cells.
The (pro)renin receptor [(P)RR] upregulates cyclooxygenase-2 (COX-2) in inner medullary collecting duct (IMCD) cells through ERK1/2. Intrarenal COX-2 and (P)RR are upregulated during chronic ANG II infusion. However, the duration of COX-2 and (P)RR upregulation has not been determined. We hypothesized that during the early phase of ANG II-dependent hypertension, membrane-bound (P)RR and COX-2 are augmented in the renal medulla, serving to buffer the hypertensinogenic and vasoconstricting effects of ANG II. In Sprague-Dawley rats infused with ANG II (0.4 μg·min(-1)·kg(-1)), systolic blood pressure (BP) increased by day 7 (162 ± 5 vs. 114 ± 10 mmHg) and continued to increase by day 14 (198 ± 15 vs. 115 ± 13 mmHg). Membrane-bound (P)RR was augmented at day 3 coincident with phospho-ERK1/2 levels, COX-2 expression, and PGE2 in the renal medulla. In contrast, membrane-bound (P)RR was reduced and COX-2 protein levels were not different from controls by day 14. In cultured IMCD cells, ANG II increased secretion of the soluble (P)RR. In anesthetized rats, COX-2 inhibition decreased the glomerular filtration rate (GFR) and renal blood flow (RBF) during the early phase of ANG II infusion without altering BP. However, at 14 days of ANG II infusions, COX-2 inhibition decreased mean arterial BP (MABP), RBF, and GFR. Thus, during the early phase of ANG II-dependent hypertension, the increased (P)RR and COX-2 expression in the renal medulla may contribute to attenuate the vasoconstrictor effects of ANG II on renal hemodynamics. In contrast, at 14 days the reductions in RBF and GFR caused by COX-2 inhibition paralleled the reduced MABP, suggesting that vasoconstrictor COX-2 metabolites contribute to ANG II hypertension.
Background: Manual qualitative and quantitative measures of terminal duct lobular unit (TDLU) involution were previously reported to be inversely associated with breast cancer risk. We developed and applied a deep learning method to yield quantitative measures of TDLU involution in normal breast tissue. We assessed the associations of these automated measures with breast cancer risk factors and risk. Methods: We obtained eight quantitative measures from whole slide images from a benign breast disease (BBD) nested case–control study within the Nurses' Health Studies (287 breast cancer cases and 1,083 controls). Qualitative assessments of TDLU involution were available for 177 cases and 857 controls. The associations between risk factors and quantitative measures among controls were assessed using analysis of covariance adjusting for age. The relationship between each measure and risk was evaluated using unconditional logistic regression, adjusting for the matching factors, BBD subtypes, parity, and menopausal status. Qualitative measures and breast cancer risk were evaluated accounting for matching factors and BBD subtypes. Results: Menopausal status and parity were significantly associated with all eight measures; select TDLU measures were associated with BBD histologic subtype, body mass index, and birth index (P < 0.05). No measure was correlated with body size at ages 5–10 years, age at menarche, age at first birth, or breastfeeding history (P > 0.05). Neither quantitative nor qualitative measures were associated with breast cancer risk. Conclusions: Among Nurses' Health Studies women diagnosed with BBD, TDLU involution is not a biomarker of subsequent breast cancer. Impact: TDLU involution may not impact breast cancer risk as previously thought.
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