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There is limited data on sex differences in renal hemodynamics and autoregulation (AR). We assessed renal vascular resistance (RVR) and renal AR in conscious male (M) and female (F) rats with intact kidneys, uninephrectomy (UNX), and UNX administered deoxycorticosterone acetate (DOCA)+salt. The susceptibility to hypertension-induced renal damage (HIRD) was also assessed in rats with UNX administered DOCA+salt. We hypothesized that M rats exhibit a lower RVR, weaker renal AR responses, and an increased susceptibility to HIRD.Sprague-Dawley rats (8-11-week-old) administered a 0.4% NaCl chow diet and water ad libitum were used. Blood pressure (BP, DSI) and renal blood flow (RBF, Transonic) were assessed in conscious rats with intact kidneys (n=12M,13F) and in rats with UNX (n=7M,8F) before and during 1 week of DOCA (3.3 mg/day s.c.) + salt (1% NaCl in drinking water). RVR was calculated as BP/RBF. Renal AR responses (fractional Δ in RBF / fractional Δ in BP) at 2.5 seconds and 20 seconds following spontaneous BP fluctuations ≥ ±5 mmHg were calculated as recently described (PMID 31792155). A 2-way ANOVA with Sidak post hoc analysis was used to assess differences among groups. Data are mean±SE, and P NIH (HL154067) and East Tennessee State University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PDF file - 135K, Supplementary Figure 1. Flow chart for patient selection and different tested performed.

Purpose: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer involving the TFEB/TFE3 genes. We aimed to investigate the genomic and epigenetic features of this entity.Experimental Design: Cytogenomic analysis was conducted with 250K single-nucleotide polymorphism microarrays on 16 tumor specimens and four cell lines. LINE-1 methylation, a surrogate marker of DNA methylation, was conducted on 27 cases using pyrosequencing.Results: tRCC showed cytogenomic heterogeneity, with 31.2% and 18.7% of cases presenting similarities with clear-cell and papillary RCC profiles, respectively. The most common alteration was a 17q gain in seven tumors (44%), followed by a 9p loss in six cases (37%). Less frequent were losses of 3p and 17p in five cases (31%) each. Patients with 17q gain were older (P = 0.0006), displayed more genetic alterations (P < 0.003), and had a worse outcome (P = 0.002) than patients without it. Analysis comparing gene-expression profiling of a subset of tumors bearing 17q gain and those without suggest large-scale dosage effects and TP53 haploinsufficiency without any somatic TP53 mutation identified. Cell line–based cytogenetic studies revealed that 17q gain can be related to isochromosome 17 and/or to multiple translocations occurring around 17q breakpoints. Finally, LINE-1 methylation was lower in tRCC tumors from adults compared with tumors from young patients (71.1% vs. 76.7%; P = 0.02).Conclusions: Our results reveal genomic heterogeneity of tRCC with similarities to other renal tumor subtypes and raise important questions about the role of TFEB/TFE3 translocations and other chromosomal imbalances in tRCC biology. Clin Cancer Res; 19(17); 4673–84. ©2013 AACR.

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PDF file - 130K, Supplementary Figure 3. A) Gene Set enrichment Analysis (GSEA) showing enrichment of mitosis pathways in cases with 17q gain. B, Ingenuity Pathway Analysis of genes expressed differently between samples with partial 17q gain and without it showing activation of ICOS-ICOSL signaling in T helper cells and activation of the CTLA4 signaling pathway.

PDF file - 86K, Supplementary Table 1. Clinicopathologic characteristics of patients with confirmed Translocation RCC Supplementary Table 2: Clinicopathological features of TFE3 overexpressing renal cell carcinoma with no TFE3 translocation identified. Supplementary Table 3: List of upstream regulators predicted to be activated or inhibited in two cases of translocation renal cell carcinoma with concomitant 17q gain and 17p loss as compared to two cases with balanced karyotype.

PDF file - 166K, Supplementary Figure 2. A, virtual karyotyping of the UOK109 cell line shows the following copy number alterations: +2, +5q,+7,-8p,+8q,-9p,+16, which are consistent with pRCC karyotyping. B, virtual karyotyping of the UOK146 cell line shows 3p loss, 9 p loss, 17 p loss and 17 gain. C, conventional karyotyping of the UOK146 cell line shows the following alterations: M1 = del(1p), M2 = del(3p), M3 = del(6q), M4 = i(17q), and M5 = t(X;1)(p11.2;q21.2). D, FISH result for TFE3 split in the novel MDA-92 cell line.

Ang II is thought to play a prominent role in the development of hypertension-induced renal disease via BP dependent and independent pathways; however the quantitative relationships between BP and renal injury have not been rigorously examined in Ang II-induced hypertension. The major goals of the present study were to assess: 1) the relationship between BP and renal injury in rats with hypertension induced by Ang II vs. renal mass reduction (RMR) and 2) the pressure-flow relationships in conscious Ang II-infused rats. One group of male Sprague-Dawley rats (Charles River) were implanted with a BP radiotransmitter and 10 days later administered Ang II (n=12; 500 ng/kg/min via osmotic minipump) or subjected to 3/4 RMR via right uninephrectomy + infarction of ∼ 1/2 of the left kidney (RKI, n=5). BP was measured continuously and kidneys were perfused fixed at 6 weeks for the assessment of renal injury. In a separate experiment, MAP and RBF (Transonic) were measured in conscious chronically instrumented rats. After recovery from surgery (∼7 days), baseline MAP and RBF were assessed (∼4 hours @ 200 Hz) on 2 consecutive days. Subsequently, rats were administered Ang II (n=6; 500 ng/kg/min) or saline (n=7; sham) via osmotic minipump and MAP and RBF were again assessed every 2-3 days for 10 days. Despite a higher average systolic BP over 6 weeks in Ang II (174±3 mmHg) vs. RKI (165±6 mmHg) rats, glomerulosclerosis (GS) was higher (p