Thesis (Ph. D.)--University of Wisconsin--Madison, 1969. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.S.)--University of Wisconsin--Madison, 1970. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Hypertension is both a domestic and international health issue – diagnosed in 1 in 3 U.S. adults and classified by the World Health Organization as the number one risk factor for mortality worldwide. It has been established that salt plays a role in the development of hypertension, and that a salt-sensitive phenotype indicates heightened sensitivity to salt consumption. Here, we studied the roles of the afferent renal nerves, which travel from the kidney to the central nervous system, and the sodium-chloride cotransporter in fluid and electrolyte homeostasis and blood pressure regulation. Our laboratory utilized a novel technique of afferent renal nerve ablation on Sprague-Dawley rats to examine the effects of afferent renal nerve mechanoreceptors and chemoreceptors in response to acute sympathoinhibitory challenges. Additionally, salt-sensitive and salt-resistant rats were randomly subjected to chronic normal salt (0.6% NaCl) or high salt (8% NaCl) diets, and examined for levels of norepinephrine and substance-P release. A different group of salt-resistant and salt-sensitive rats were subcutaneously infused with terazosin, a selective -1 adrenoreceptor antagonist, or propranolol, a selective -adrenoreceptor antagonist, and then randomly subjected to normal salt (0.6% NaCl) or high salt (4% NaCl) diets for 21 days. We subsequently examined these rats, and analyzed the effects of high salt intake on blood pressure, sodium-chloride cotransporter activity, and expression of the sodium-chloride cotransporter and its relevant kinases. In response to an acute mechanoreceptor-specific stimulus, Sprague-Dawley rats that underwent afferent renal nerve ablation were unable to modulate blood pressure or natriuresis after regaining consciousness. Chronic high salt (8% NaCl) consumption in salt-sensitive rats resulted in increased levels of plasma norepinephrine, renal norepinephrine, and norepinephrine-evoked Substance-P release. In addition, salt-sensitive rats subjected to a 21-day high salt (4% NaCl) diet exhibited increased blood pressure, elevated sodium-chloride cotransporter activity, and upregulated levels of the sodium-chloride cotransporter and the kinases that regulate it. However, these observed increases in blood pressure, protein activity, and protein expression were abolished in salt-sensitive rats experiencing -1 adrenoreceptor antagonism due to terazosin administration. In conclusion, our findings indicate that mechanoreceptor-driven afferent renal nerve activation is needed to maintain fluid and electrolyte homeostasis and regulate blood pressure in response to acute sympathoinhibitory challenges and chronic high salt intake. In addition, our data demonstrates that the sodium-chloride cotransporter is aberrantly upregulated in salt-sensitive rats through a norepinephrine-1-adrenoreceptor gated pathway, and this this upregulation results in excessive salt reabsorption. Thus, our experiments have generated new data that reveals selective 1-adrenoreceptor antagonism and renal denervation as potential treatment options for hypertensive individuals.

It is well established that exposure to adverse environments in early life including both maternal under and over-nutrition predisposes individuals to similar adverse traditionally adult onset diseases such as the metabolic syndrome. Epidemiological observations and animal models have highlighted that early life exposure to maternal under-nutrition has a detrimental effect on offspring kidney health. The prevalence of chronic kidney disease has increased rapidly in recent years, concurrently with the growing obesity epidemic. Obesity is now prevalent in all age groups within the population including women of child-bearing age. Despite this, the effect of early life exposure to maternal obesity on long-term kidney health has not been investigated in humans. Studies in animals have demonstrated that exposure to early life under-nutrition programs the offspring kidney. Offspring exposed to maternal calorie restriction or a low protein diet typically display a reduced number of nephrons and increased glomerular areas. No studies to date have investigated the effect of maternal obesity on early life kidney and glomerular morphology. To address this, as part of this thesis, kidney morphology was assessed at weaning in male mice exposed to maternal diet-induced obesity throughout gestation and lactation. There was no effect of maternal diet on the number of nephrons counted within a distinct region in the offspring kidneys. However, glomerular density was decreased and glomerular area was increased in offspring exposed to maternal obesity. Alterations in renal morphology in early life have been linked to hypertension and renal disease in adulthood in both epidemiological and animal studies. Therefore, a second aim of this thesis was to assess blood pressure, renal function and markers of renal damage in offspring exposed to maternal obesity throughout the life-course. Post-pubescent male offspring (8 weeks of age) exposed to maternal obesity displayed increased blood pressure but no signs of renal dysfunction or damage. However, by six months of age offspring exposed to maternal obesity had increased glomerulosclerosis and tubulointerstitial fibrosis. The obesity epidemic is attributed to a shift in behaviours towards consumption of energy dense foods and inactivity. In addition, evidence from human and animal studies has highlighted that exposure to maternal obesity primes offspring to prefer sugary and fatty foods and to consume more calories. As such, offspring exposed to maternal obesity are likely to encounter an obesogenic environment in later life. A third aim of this thesis was therefore to determine the effect of maternal obesity in combination with a post-weaning obesogenic diet on offspring kidney health. To address this aim, offspring either exposed to an obesogenic diet or control diet throughout pregnancy and lactation were weaned onto either an obesogenic or control diet themselves. Six month old offspring exposed to a post-weaning obesity alone displayed indices of renal dysfunction and damage including glomerulosclerosis and tubulointerstitial fibrosis. Importantly, exposure to maternal obesity exacerbated the renal fibrosis in offspring exposed to a post-weaning obesogenic diet. With the growing prevalence of maternal obesity globally, there is great interest in determining an effective intervention to prevent adverse health outcomes in exposed individuals. The Ozanne laboratory has shown that maternal exercise in obese dams during pregnancy reduces maternal serum insulin and offspring insulin to control levels, highlighting that maternal exercise may be a promising intervention to limit adult-onset diseases in offspring exposed to early life obesity. The final aim of this thesis was to therefore assess the effect of exercise during an obese pregnancy on markers of offspring renal development during late gestation. Gene markers of ureteric bud branching, an important precursor of nephrogenesis, were increased in fetuses exposed to maternal obesity with exercise as opposed to obesity alone. Additionally one of these gene markers correlated negatively with maternal insulin levels. Protein markers indicative of an active ureteric bud branching pathway were also increased in offspring exposed to maternal obesity with exercise. In conclusion, studies conducted in this thesis demonstrate that offspring exposed to maternal obesity show alterations in renal morphology in early life and are predisposed for renal disease in later life, especially when they are challenged with a post-weaning obesogenic diet. Maternal exercise might be an effective intervention to rescue offspring renal morphology and later life health associated with maternal obesity, however this requires further investigation. These results have important implications for future generations within the setting of an ever increasing obesity epidemic and a growing prevalence of chronic kidney diseases.

Non-steroidal Antiinflammatory Drugs have been shown to play an important role in the chemotherapeutic prevention of Colorectal Cancer. Their mechanism in doing so has been proven as far as scientific works today allow results and an understanding of this mechanism. Without a doubt, many aspects of this drug in terms of chemotherapy tailored to the treatment of Colorectal Cancer remain to be illuminated and are subject to further investigations. Whether a cyclooxygenase inhibitor can be used as a chemopreventive agent needs to be assessed in each case individually and the whole view of a patient must be taken into account considering his overall status of health and the exclusion of the potential harm of side effects. Given the fact that these drugs provide protection of Colorectal Cancer to a certain extent, their use will most probably increase in countries where they are easily accessable.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / O elevado consumo de sÃdio na dieta tem aumentado consideravelmente nas Ãltimas dÃcadas, promovendo o desenvolvimento de diversas doenÃas crÃnicas, como hipertensÃo arterial, acidente vascular cerebral e doenÃas coronarianas. PeptÃdeos como a urodilatina (UD) e uroguanilina (UGN) tÃm sido implicados na regulaÃÃo da homeostase de sal e Ãgua. PorÃm, os mecanismos de regulaÃÃo ainda nÃo foram bem esclarecidos, assim como suas interaÃÃes na funÃÃo renal. O objetivo desse trabalho à estudar os principais efeitos dos peptÃdeos UD e UGN em rins de ratos submetidos a alta ingestÃo de NaCl. Os efeitos foram examinados usando ratos Wistar mantidos por 10 dias em gaiolas metabÃlicas. O grupo controle recebeu somente Ãgua destilada, enquanto que o grupo tratado recebeu 2% de soluÃÃo de NaCl. A funÃÃo renal foi avaliada atravÃs da perfusÃo de rim isolado de ratos. Os dados foram comparados atravÃs de teste t de Student e ANOVA, com significÃncia de 5%. A UD promoveu reduÃÃo da pressÃo de perfusÃo, resistÃncia vascular renal e fluxo urinÃrio, foi observado tambÃm aumento da excreÃÃo de sÃdio e cloreto, sendo as alteraÃÃes mais proeminentes ao nÃvel distal. Contudo, apÃs tratamento com sal os efeitos da UD nÃo foram vistos, observou-se um aumento transporte de sÃdio e cloreto mais pronunciado ao nÃvel proximal. Os efeitos da UGN tambÃm foram avaliados na presenÃa do sal, onde foram observados a elevaÃÃo da pressÃo de perfusÃo, fluxo urinÃrio e ritmo de filtraÃÃo glomerular; seguido de aumento na excreÃÃo de sÃdio e cloreto, principalmente ao nÃvel de tÃbulo proximal. Os resultados tambÃm demonstraram a expressÃo aumentada de mRNA do receptor GC-C e uma discreta reduÃÃo na expressÃo de GC-A em ratos tratados com sal. ApÃs uma ingestÃo aumentada de sal, sÃo ativadas vias fisiolÃgicas muito bem reguladas no objetivo de eliminar o excesso de sÃdio. A UGN parece ser o hormÃnio primordial envolvido nessa via, contudo a UD apresentam tambÃm participaÃÃes nesse processo. O receptor GC-C està diretamente envolvido na regulaÃÃo desses processos fisiolÃgicos

Abstract The aim of the present work was to elucidate the incidence, associated risk factors and natural course of nephrocalcinosis (NC) in very low birth weight (VLBW) infants, and to evaluate renal function in affected infants during early childhood. The occurrence and course of NC in full-term infants receiving furosemide and in infants with congenital lactase deficiency were also studied. A total of 129 VLBW infants were screened for NC by renal ultrasonography (US) at 2 and 6 weeks and 3 months, and ultrasonic follow-up was performed on the infants with NC at 6, 12, 18 and 24 months, and thereafter annually up to age 5-6 years or until ultrasonic resolution. NC was classified according to its pyramidal localisation and extent. Twenty VLBW children with neonatal NC and 20 control pairs without the condition were examined for renal function at 4.7 (SD 1.1) vs. 4.6 (0.9) years of age. Thirty-six full-term infants who had received furosemide treatment for congestive heart failure for at least 4 weeks and 36 control infants without any diuretic therapy were examined by renal US and by means of a random urine sample taken at a median age of 2.9 vs. 3.4 months. The case records of the 11 infants with congenital lactase deficiency were analysed for NC, and these children were re-evaluated at 2 to 10 years of age. NC was detected in 26 out of the 129 VLBW infants (20%). The infants with NC were sicker and smaller than the unaffected ones and had more often received furosemide, dexamethasone and theophylline treatment. NC was peripheral in 14 cases (54%), scattered in 7 (27%) and extensive in 5 (19%). All the casesof peripheral NC showed resolution at 12 months, but abnormal renal findings were seen in 3 out of the 7 with scattered NC and 3 out of the 4 surviving children with extensive NC at 24 months, in 2 of whom the condition persisted at age 5-6 years. The children with neonatal NC showed increased urinary calcium and μ2-microglobulin excretion as compared with the controls in early childhood, but there was no significant difference in distal tubular acidification capacity, nor in estimated creatinine clearance. Five out of the 36 full-term infants receiving long-term furosemide had NC, but none of the controls. The daily dose of furosemide and the urinary calcium concentration were both higher in the infants with NC. Abnormal renal findings were still visible in two of the cases at 24 months of age. Hypercalcaemia was found in 7 out of 10 infants with congenital lactase deficiency tested at the time of diagnosis, and NC was seen in 5 of the 7 cases examined by renal ultrasonography. No constant dysfunction in calcium homeostasis was seen at re-evaluation, but nephrocalcinotic changes were observable in 3 out of the 11 children. NC may complicate not only the course of VLBW infants, but also that of full-term infants with calciuric medication and diseases that involve hypercalcaemia. Some renal tubular dysfunction may result from NC in former preterm infants, but overall kidney function seems not to be seriously compromised in early childhood.

4 pp. / Calcium is an essential mineral found in great abundance in the body. Ninety-nine percent of all the calcium in the body is found in the bones and teeth. The remaining one percent is in the blood. Calcium plays important roles in nerve conduction, muscle contraction, and blood clotting. If calcium levels in the blood drop below normal, calcium will be taken from bone and put into the blood in order to maintain blood calcium levels. Therefore, it is important to consume enough calcium to maintain adequate blood and bone calcium levels. Revised 2017, Revised 2011, Original 2004

Certain investigations were undertaken on the kidneys of various birds using that of the domestic fowl, as a type; and, where possible, comparing the results with those reported for other classes of animals. The vascular system was considered, to establish the statement of Spanner (1924), that the bird kidney possesses a renal portal system. Embryological, histological, and anatomical evidence, were brought forward in favour of this venous arrangement. The histology was examined with different techniques. In this connection, a comparative examination of fixation fluids was undertaken, as difficulty was experienced in the histological examination of bird kidney tissue. The histological results indicated some degree of glomerular degeneration and an Increase in proximal tubule development as compared to that of the mammal. Cytological studies were carried out on mitochondria and the Golgi apparatus. The mitochondria of the domestic fowl, and the pigeon, showed great concentration in the cells of the proximal tubule. The Golgi apparatus was investigated in the fowl; and showed a development in the cells of the proximal segment of the nephron, in excess of that in the mammal. The conclusion deduced from both these cytological studies, indicated an increase in activity of the proximal segment in the bird, over that of the mammal. A histochemical test using alkaline phosphatase, was performed, to decide whether the reported glomerular degeneration in the bird is such that glucose elimination is reduced or absent. Alkaline phosphatase is an enzyme stated to assist in the reabsorption of glucose eliminated by glomerular filtration. The results were compared with those of the classes possessing good glomerular development. It was noted that the avian kidney shows considerable evidence of alkaline phosphatase activity. Two conclusions are reached: (1) That the bird kidney shows definite evidence of tubular activity. (2) That in spite of apparent signs of degeneration, the glomerulus in the avian kidney functions comparably to that of the mammal. / Science, Faculty of / Zoology, Department of / Graduate

The histochemical localisation of ATPase enzymatic activity at the level of the electron microscope was carried out on adult and newborn kidney tissue pre-fixed in 5% glutaraldehyde buffered with 0.1 M sodium cacodylate. Both the lead method at pH 7.2 and the calcium method at pH 9.4 were used. The effects of the modifiers PHMB and L-cysteine were also studied. In the adult rat kidney, the observations of other investigators on kidney ATPase activity were substantiated. Reaction precipitate was localised at the brush border of the proximal tubules, the membranes of the basal and lateral interdigitations of the proximal and distal tubules, and the plasma membranes of the podocytic foot processes. PHMB exerted an inhibitory effect on distal tubular activity at both pH 7.2 and pH 9.4, while cysteine was inhibitory only at pH 9.4. Glomerular ATPase activity was inhibited by PHMB and L-cysteine at pH 9.4. In the newborn rat kidney, ATPase enzymatic activity was observed in the tubular elements as well as in the glomeruli. In the undifferentiated tubules, reaction product was abundant on the lateral membranes between individual cells. The luminal and basal plasma membranes, which were simple in contour, showed little or no accumulation of precipitate. However, as the microvilli became long and slender in the early stages of the differentiation of the brush border, there was a concomitant increase in the intensity of the ATPase enzymatic reaction. Similarly, reaction product became associated with the developing basal interdigitations. In the immature glomerulus, reaction precipitate was most often observed where two sets of membranes were in apposition. With differentiation, enzymatic activity was localised primarily on the podocytic foot processes. The localisation of ATPase activity at pH 9.4 was found to be influenced by the time of pre-fixation in glutaraldehyde while ATPase activity at pH 7.2 was not affected. At pH 7.2, neither tubular nor glomerular ATPase enzymatic activity responded to PHMB or L-cysteine. For both adult and newborn kidneys, the correlation between structure and function was briefly considered. The adult kidney is an important and efficient homeostatic organ. In urine formation various substances are transported across the cell membranes of the glomeruli and tubules. Ultrastructurally, the glomeruli and tubules show modifications characteristic of cells engaged in active transport processes. There is a large increase in plasma membrane surface area, as exemplified by the intricate inter-digitations of the podocytic foot processes, the elaborate basal and lateral infoldings, and the brush border of the proximal tubules. Much ATPase activity was found associated-with these plasma membranes. The newborn kidney is not as efficient as the adult kidney in maintaining body homeostasis. It is not only functionally but also morphologically immature. Most of the tubules and glomeruli are undifferentiated and do not show specialisations of the plasma membranes as seen in the adult kidney. There is also a relatively smaller amount of ATPase present in the newborn kidney. For both adult and newborn kidneys, it was postulated that at least two types of ATPases with different pH optima are present on the plasma membranes of the tubules and glomeruli. / Medicine, Faculty of / Graduate