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Cardiovascular and Renal Cell BiologyHead: Dr Jane BlackPhD Students: Ms Lina Gubhaju, Ms Vladislava ZohdiMasters student: Oksan Gezmish. Part-time research Assistant: Kyungjoon Lim and Laura Stamp
Cardiovascular disease is the leading cause of morbidity and mortality in Australia. Our research focuses on the cell biology of the cardiovascular system (including the heart, large and small blood vessels) and the kidney, which is intimately associated with blood pressure control. We are particularly interested in the causes of hypertension (a sustained elevation in blood pressure) and left ventricular hypertrophy (enlargement of the pumping chamber of the heart), which are both major risk factors for the development of cardiovascular disease. Currently the main research projects in our laboratory are: Low birth weight, nephron deficit and the pathogenesis of hypertension and renal disease
Population studies have shown an association between low birth weight and the development of hypertension and renal disease later in life. The nephrons are the functional units of the kidney. We and others have shown that intrauterine growth restriction leads to underdevelopment of the kidneys resulting in a deficit in nephron endowment at birth. It is our hypothesis that this reduction in nephron endowment predisposes to the development of hypertension and renal disease later in life. By administration of a low protein diet to rats during pregnancy we are able to induce low birth weight and reduced nephron endowment in the offspring. We are currently investigating kidney development in these offspring and looking at the effects on adult blood pressure and renal function later in life. The renal function studies are being performed in collaboration with Dr Kate Denton in the Department of Physiology at Monash University. In particular, we are investigating how a reduced nephron endowment renders the kidney susceptible to postnatal insults. Much of this work has been performed in our laboratory by Dr Monika Zimanyi whilst undertaking her PhD. Monika has recently been awarded her PhD with her thesis focused on this research theme. She has shown in a comprehensive series of experiments (that were performed in collaboration with Dr Kate Denton in the Department of Physiology at Monash University and with Dr Josephine Forbes at the Baker Heart Research Institute) that rats with a developmental nephron deficit due to maternal protein restriction are more susceptible to the renal injury associated with elevated circulating of advanced glycation endproducts. Advanced glycation endproducts form naturally during ageing and circulate in the bloodstream. When there is elevation in blood glucose levels, as seen with diabetes, there is a marked elevation of advanced glycation endproducts in the circulation. These advanced glycation endproducts are linked to the pathogenesis of diabetic renal disease. Hence, the findings of Monika’s experiments suggest that babies born with a reduced nephron endowment are more susceptible to advanced glycation endproduct renal injury and diabetic renal disease. We have also been undertaking a number of studies looking at the effect of late gestational growth restriction on kidney development in fetal lambs. Interestingly, we have shown that if growth restriction occurs late in gestation that nephron endowment is not affected since nephrogenesis is already complete at the onset of the growth restriction. In the undertaking of these studies we have observed differences in the morphology of the growth-restricted kidneys when compared to the non-growth restricted control kidneys. Ms Vladaslava Zhodi, an Honours student in our laboratory is currently investigating these morphological differences. Recent publications from our laboratory in this area:Zimanyi MA. Bertram JF, Black MJ. Nephron number and blood pressure in rat offspring with maternal high-protein diet. Pediatr Nephrol. 2002, 17:1000-1004 Black MJ, Wang Y, Bertram JF. Nephron endowment and renal filtration surface area in young spontaneously hypertensive rats. Kidney Blood Press. Res. 2002, 25:20-26 Black MJ, Briscoe TA, Constantinou M, Kett MM, Bertram JF. Is there an association between the level of adult blood pressure and nephron number or renal filtration surface area? Kidney Int. 2004, 65:582-588. Mitchell EKL, Louey S, Cock ML, Harding R, Black MJ. Nephron endowment and filtration surface area in the kidney after growth restriction of fetal sheep. Pediatr Res. 2004; 55: 769-773 Zimanyi MA, Bertram JF, Black MJ. Does a nephron deficit in rats predispose to salt-sensitive hypertension? Kidney Blood Press Res. 2004; 27: 239-247 Zimanyi MA, Denton KM, Forbes JM, Thallas-Banke V, Thomas MC, Poon F, Black MJ, A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products. Diabetologia 2006; 49:801-810. Epub 2006. Feb 23. Kidney development in premature babies: With the improvements in medical technology the gestational age with which premature babies can be kept alive continues to decrease. We are particularly interested in the development of the kidneys in premature babies since nephrogenesis, the formation of nephrons, occurs predominantly in the third trimester of pregnancy, with nephrogenesis complete at term. No new nephrons are formed in the kidney of term babies after birth. As the nephrons are the fundamental filtering units of the kidney it has been imperative to establish whether nephrogenesis continues after birth in babies born prematurely. In collaboration with the University of Texas Health Science Centre at San Antonio, we are investigating kidney development in prematurely delivered baboons. Similar, to humans these prematurely delivered baboons have been placed in humidified cribs and ventilated after birth. These studies are being performed by Ms Lina Gubhaju, a post-graduate student in our laboratory. Lina has recently shown that the baboon is an excellent model for studies of kidney development in humans, with nephrogenesis in the baboon kidney predominantly occurring in the third trimester and it is complete by late in gestation. This study has recently been accepted for publication (see below). Recent publications from our laboratory in this area:Gubhaju L, Black MJ. The baboon as a good model for studies of human kidney development. Pediatr Res. 2005; 58:505-509. Low birth weight, reduced cardiomyocyte number and the pathogenesis of cardiac disease: Many population studies have shown an association between low birth weight and the development of heart disease later in life. In our laboratory we are undertaking a number of studies in animal models looking at potential causes of adult heart disease in offspring that were growth-restricted in utero. Importantly, cell division of the heart muscle cells (cardiomyocytes) mainly occurs prior to birth. Growth of the heart muscle after birth is predominantly due to enlargement of the cardiomyocytes and not by cell division. We have recently shown that intrauterine growth restriction in rats leads to a reduced number of cardiomyocytes at birth. We suggest that if there are fewer cardiomyocytes in the intrauterine growth restricted heart this may lead to adverse effects in the heart later in life, especially if the adult heart undergoes further enlargement as seen with obesity or following the development of hypertension. Kyung Joon Lim, an Honours student in our laboratory last year has looked at the effects of intrauterine growth restriction, due to maternal protein restriction on the pathology of the heart in adulthood. He found that there was a significant increase in the amount of collagen (fibrosis) in the adult heart of rats that were growth-restricted in utero. Increased fibrosis is linked to malfunction of the heart muscle and to cardiac arrythmias. In addition, in collaboration with Prof Richard Harding, Dr Marianne Tare, Dr Helena Parkington and Dr Miodrag Dodic in the Department of Physiology at Monash University we are investigating in the sheep model the effect of late gestational intrauterine growth restriction on the structure of the heart at birth, a few weeks after birth and in adulthood. We are especially interested in seeing how the intrauterine growth restricted heart responds in adulthood when it is challenged to enlarge due to the development of hypertension (high blood pressure). Recent publications from our laboratory in this area: Brandt Corstius H, Zimanyi MA, Maka N, Herath T, Thomas W, van der Laarse A, Black MJ. The effect of intrauterine growth restriction on the number of cardiomyocytes in the rat heart. Pediatr Res. 2005; 57:796-800. Left ventricular hypertrophy is a major independent risk factor for cardiovascular disease, irrespective of race, gender and level of blood pressure. This may in part be attributed to the development of fibrosis and / or ischemia in the heart in the enlarged left ventricle. Angiotensin II is a vasoactive hormone that has growth promoting effects in the heart. Angiotensin II acts via two main receptor types the angiotensin type 1 (AT1) receptor and the angiotensin type 2 (AT2) receptor. Angelo D’Amore, a PhD student in our laboratory, has been investigating the effects of angiotensin II, acting via the AT2 receptor on capillarisation and on the development of fibrosis in the left ventricle of genetically hypertensive rats. These studies are being performed in collaboration with Dr Rob Widdop and Dr Emma Jones in the Department of Pharmacology at Monash University. In addition, Angelo has been working with Dr Walter Thomas, at the Baker Heart Research Institute where he has developed an AT2 receptor adenovirus. Using this technology, he has been looking at the direct effect of AT2 receptor stimulation in cultured cardiomyocytes following upregulation of the AT2 receptor. Recent publications from our laboratory in this area: Jones EM, Black MJ, Widdop RE. Angiotensin AT2 receptor contributes to cardiovascular remodelling of aged rats during chronic AT1 receptor blockade, J Mol Cell Cardiol. 2004; 37: 1023-1030. Other recent publications from our laboratory in the area of cardiovascular research: Dunstan HJ, Briscoe TA, Bertram JF, Johnston CI, Black MJ. Angiotensin-converting enzyme inhibition in adult hypertensive rats: a stereological study of renal filtration surface area. Clin Exp Pharmacol Physiol. 2003, 30:72-76.
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