Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The purpose of this study was the identification of science principles underlying the care of a patient with glomerulonephritis and the nephrotic syndrome and the deduction of appropriate nursing activities from these principles. The four sciences of anatomy, physiology, pathology and biochemistry were included in this study. / 2031-01-01

Dragon (RGMb) is one of the three repulsive guidance molecule (RGM) family members RGMa, RGMb (Dragon) and RGMc (hemojuvelin). RGM family members are glycophosphatidylinositol (GPI)-anchored membrane proteins. The three RGM proteins have been identified as co-receptors that enhance BMP-Smad signaling. Previous studies showed that Dragon protein is expressed in the epithelial cells of kidney tubules including collecting ducts, distal convoluted tubules and thick ascending limbs, and that Dragon enhances BMP4 signaling in tubular epithelial cells. However, the biological roles of Dragon in the renal epithelial cells are yet to be defined. / We now showed that overexpression of Dragon inhibited E-Cadherin expression, but did not affect epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 in mouse inner medullary collecting duct (IMCD3) cells. Dragon also increased cell death induced by hypoxia in association with increased cleaved PARP and cleaved Caspase-3 levels in IMCD3 cells. Dragon did not have any effect on the expression of inflammatory factors in IMCD3 cells. Previous studies suggest that the three RGM members can also function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-Cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. / Dragon expression in the kidney was upregulated by unilateral ureteral obstruction (UUO) in mice. Compared with wild-type mice, heterozygous Dragon knockout mice exhibited 45-66% reduction in Dragon mRNA expression, decreased epithelial cell apoptosis, increased tubular E-Cadherin expression, and had attenuated tubular injury after UUO. UUO-induced renal fibrosis and inflammation did not change between wild-type mice and heterozygous Dragon knockout mice. Similar results were obtained in the model of ischemia-reperfusion kidney injury. Compared with wild-type mice, heterozygous Dragon knockout mice showed decreased epithelial cell apoptosis. Ischemia-induced renal fibrosis and inflammation did not change between wild-type mice and heterozygous Dragon knockout mice. / Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial cell apoptosis both in vitro and in vivo. / Dragon (又稱排斥導向分子b) 是排斥導向分子家族中的一員。這個家族包括排斥導向分子a，排斥導向分子b (又稱Dragon) 和排斥導向分子c (又稱血幼素) 三名成員。它們都是一種磷脂酰肌醇(GPI) 錨定蛋白。研究發現，這三種排斥導向分子都可以作為輔助受體來加強骨形成蛋白信號通路。我們之前的研究發現，Dragon在集合管、遠曲小管和髓袢升支粗段的上皮細胞內都有表達，同時Dragon增強腎小管上皮細胞中骨形成蛋白(BMP)4的信號轉導。但是，Dragon在腎小管上皮細胞中的生物學功能尚不清楚。 / 我們的研究結果表明，Dragon過量表達后降低腎內髓集合管上皮細胞中上皮型鈣粘素 (E-Cadherin) 的表達，但是不影響轉化生長因子-β1誘導的上皮細胞向間充質細胞的轉化。在低氧的條件下，Dragon促進腎內髓集合管上皮細胞的死亡并同時增加活化的多聚二磷酸腺苷酸核糖聚合酶（PARP）和半胱天冬酶3 (Caspase-3) 的量。但是Dragon對腎內髓集合管上皮細胞分泌的免疫因子沒有影響。之前的研究表明，neogenin是這三個導向排斥分子的受體。同樣在我們的研究中發現，Dragon是通過neogenin受體而不是骨形成蛋白信號通路來影響腎內髓集合管上皮細胞的死亡和E-Cadherin的表達。 / 單側輸尿管結扎手術后，在受損傷的小鼠腎臟中Dragon的表達升高。與野生型的小鼠相比，雜合型Dragon敲除小鼠中Dragon信使核糖核酸的表達下降了45-66%，腎小管上皮細胞的凋亡減少，腎小管E-Cadherin的表達升高。單側輸尿管結扎手術后野生型和雜合型Dragon敲除小鼠腎臟皆存在纖維化和炎症，但是二者沒有差異。缺血再灌注的小鼠模型實驗中得到相似的結果。與野生型的小鼠相比，雜合子Dragon敲除小鼠中腎小管上皮細胞凋亡的數目減少。同樣缺血再灌注手術后野生型和雜合子Dragon敲除小鼠腎臟都也存在纖維化和炎症，但二者沒有差異。 / 體內和體外實驗结果均表明，在腎臟損傷過程中Dragon可能損害腎小管上皮的完整性并促進腎小管上皮細胞的凋亡。 / Liu, Wenjing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 192-212). / Abstracts also in Chinese. / Title from PDF title page (viewed on 03, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Lipid accumulation is a pathological feature of every type of kidney injury. However, despite this striking histological feature, physiological accumulation of lipids in the kidney is poorly understood. We studied whether the accumulation of lipids in the fasted kidney is derived from lipoproteins or non-esterified fatty acids (NEFAs). Increasing circulating NEFAs using a beta adrenergic receptor agonist caused a 15-fold greater accumulation of lipid in the kidney, while mice with reduced NEFAs due to adipose tissue deficiency of adipose triglyceride lipase had reduced renal triglycerides. Fasting-induced kidney lipid accumulation was not affected by inhibition of lipoprotein lipase (LpL) with poloxamer 407 or by use of mice with induced genetic LpL deletion. Despite the increase in CD36 expression with fasting, genetic loss of CD36 did not alter fatty acid uptake or triglyceride accumulation. Our data demonstrate that fasting-induced triglyceride accumulation in the kidney correlates with the plasma concentrations of NEFAs but is not due to uptake of lipoprotein lipids and does not involve the fatty acid transporter CD36. A second project was initiated to assess how diabetes causes increased systemic inflammation. Calgranulins S100A8 and S100A9 circulating levels are increased during diabetes and might instigate a sterile inflammatory response in the innate immune system. To determine whether krüppel-like factor 5 (KLF5) regulates S100A8 and S100A9 during hyperglycemia; we generated myeloid-specific KLF5 knockout mice (MKK) and found these mice had no change in circulating monocytes and neutrophils. We isolated neutrophils from these mice and found that S100A8 and S100A9 expression was not changed. We found similar null results when these mice were made diabetic. We conclude that this line of myeloid-deficient KLF5 knockout mice do not have changes in S100A8 or S100A9 expression or in the numbers of circulating white cells.

Exome sequencing (ES) has empowered genetic diagnosis and novel gene discovery, and is increasingly applied as a first-line test for a variety of disorders. Chronic kidney disease (CKD) affects more than in 1 in 10 persons worldwide, resulting in high morbidity, mortality, and healthcare costs. As CKD displays substantial genetic and phenotypic heterogeneity, the unbiased approach of ES can help to pinpoint a specific etiology and thereby support personalized care. However, the broader utility of ES for nephropathy and challenges associated with such expanded implementation have yet to be systematically assessed. Here, we investigate these questions through integrating ES and phenotype data from large CKD case and control cohorts. First, we survey the genetic and clinical disease spectrum of Mendelian forms of kidney and genitourinary disease, and generate a comprehensive curated list of gene-disease pairs. We then use ES data from 7,974 self-declared healthy adults to evaluate the population prevalence of candidate pathogenic variants for Mendelian nephropathy under different analytic filtering pipelines. We observe an appreciable frequency of putatively diagnostic variants for these conditions using stringent as well as standard filters, resulting in a considerable burden for both variant interpretation and clinical follow-up. Next, we perform ES and diagnostic analysis in a combined cohort of 3,315 all-cause CKD cases. We find diagnostic variants among patients spanning clinical disease categories, and that both the primary and secondary genetic findings resulting from ES have meaningful implications for medical management. We conclude by discussing the greater insights regarding the value of ES for kidney disease emerging from our investigations, and promising avenues for subsequent studies.

No description available.

Banca: José Roberto de Oliveira e Silva / Banca:Wilma Pereira Bastos Ramos / Banca: Gerhard Malnic / Banca: Sonia Malheiros Lopes Sanioto / Banca: Frida Zaladek Gil / Resumo: Estudamos o efeito da Angiotensina II sobre a secreção de potásssio em túbulo distal final (segmento conector e duto coletor cortical) através da técnica de microperfusão estacionária in vivo e mensuração da atividade catiônica por meio de microeletrodos contendo resina de troca iônica sensível a K+. A perfusão luminal com ANG II reduziu o fluxo secretório de potássio (JK+) observado no grupo controle de 0.900.19 nmol/cm2.s, n=12, para 0.51±0.05, n=9, (ANG II 10-12M), 0.700.22, n=27 (ANG II 10-11M) e 0.630.08 nmol/cm2.s, n=12 (ANG II 10-9M); (p<0.05 teste t pareado). Entretanto, na presença de dose elevada de ANG II (10-6M) não observamos efeito significante sobre o JK+. A presença de Losartan (10-6M), um bloqueador não peptídico do receptor AT1 reverteu o efeito inibitório da ANG II. No intuito de se avaliar a possibilidade da via PLA2/ácido araquidônico/PGE2 participar deste processo de regulação celular, uma vez que tais agentes participam da inibição de outros mecanismos de transporte que envolve a ativação da sinalização celular mediada por Angiotensina II, perfundimos luminalmente PGE2 o qual inibiu o fluxo secretório de K+ em ambas doses utilizadas no presente trabalho; Jk+ controle = 0.930.08 nmol/cm2.s, n=12 para 0.550.05 nmol/cm2.s, n=12 (PGE2 10-9M) e 0.470.04 nmol/cm2.s, (PGE2 10-6M), n=12, (p<0.01). A perfusão com Indometacina (10-5M), bloqueador inespecífico da via PLA2/Ácido Araquidônico/PGE2 associado a Angiotensina II (10-9M) aumentou o JK+ (0.95±0.12 nmol.cm-2.s-1, n = 13) quando comparado a perfusão isolada de ANG II (10-9M) (Jk+ = 0.630.05 nmol/cm2.s, n = 10); (p<0.05). Concluímos que a ANG II inibiu luminalmente a secreção distal de K+ provavelmente acoplado ao receptor AT1 e este efeito pode ser mediado pela via PLA2/Acido Araquidônico/ /PGE2 / Abstract: The effect of luminal ANGII on K+ secretion by late distal tubule (connecting segment and initial cortical collecting duct) was studied using "in vivo" stationary microperfusion and K-sensitive microelectrode techniques. Luminal perfusion of ANG II reduced Jk+ from a control value of 0.900.19 (n=12) nmol/cm2.s to 0.51±0.05, n=9, (10-12M), 0.700.22, n=27 (10-11M) and 0.630.08, n=12 (10-9M) nmol/cm2.s (p<0.05 by paired t-test). However, high doses of ANGII (10-6M) had no significant effect on Jk+. Losartan 10-6M, a non-peptide AT1 receptor blocker, reverted the inhibitory effect of ANGII. To test the possibility that the PLA2/arachidonic acid/PGE2 pathway, which had been shown to inhibit other transport mechanisms, is involved in ANGII-mediated cellular signaling cascades, PGE2 was perfused luminally (Jk+ control = 0.930.08, n=12 nmol/cm2.s; 10-9M PGE2, Jk+ = 0.550.05, n-12; 10-6M PGE2, Jk+ = 0.470.04), n=12; both doses reduced K+ secretion significantly (p<0.01). Perfusing with Indomethacin, an unspecific blocker of the PLA2/arachidonic acid/PGE2 path, (10-5M), plus ANG II (10-9M), JK+ increased to 0.95±0.12 (n=13) nmol.cm-2.s-1 compared to ANG II alone (Jk+ = 0.630.05, (n=13) nmol/cm2.s, p<0.05). During luminal perfusion with Indomethacin alone, no significant effect on K+ secretion was seen (Jk+ control = 0.730.05 (n=10) nmol/cm2.s, 10-6M INDO Jk+ = 0.630.07 (n=10), P>0.19. In conclusion, ANG II is able to regulate distal K+ secretion when applied to the tubule lumen, probably via AT1 receptors; it is suggested that the signalling path of the inhibitory effect of ANG II may involve PLA2/arachidonic acid/PGE2

Abstract not available

Photocopy (Vol. 1) / 2v. : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 1981

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

No description available.