Nephrology

THE GENDER, GENES AND GLOMERULAR-BASED DISEASES

Brief Description

The Gender, Genes and Glomerulonephritis group is multidisciplinary and collaborative, and was established to elucidate factors responsible for progression of glomerular-based disease, with a focus on gender, psychosocial variables, genetics, and the renin-angiotensin system (RAS). Areas of expertise include molecular-cellular techniques, integrative biology, and epidemiology. Ongoing studies include an investigation of the impact of gender on the outcome of glomerular diseases; the relationship between RAS genotypes, gender, and blood pressure regulation; gender-mediated differences in RAS function; and the impact of estrogen on signaling in mesangial cells. The program has secured CIHR long-term funding as a New Emerging Team, and has, as a major objective, the training of research fellows.

The Diabetes group is collaborative, containing molecular/cellular, integrative, and epidemiological elements. It was established to elucidate mechanisms responsible for the initiation of renal disease in diabetic patients, focusing on genetics, blood pressure regulation and RAS function. The program includes endocrinologists at the Hospital for Sick Children.  Our dominant hypothesis is that high glucose is necessary, but not sufficient to explain the initiation of nephropathy. Ongoing studies include the relationship between diurnal blood pressure and renal hemodynamic function, and the hemodynamic response to high glucose in groups segregated by risk of nephropathy.  

Principal Investigators

Recent Original Research Publications

Reich H, Duncan JA, Weinstein J, Cattran DC, Lai V, Scholey JW, Miller JA. Interactions between gender and the angiotensin type 1 gene receptor polymorphism. Kidney Int (in press).

Krepinsky J, Ingram AJ, James LR, Ly H, Thai K, Cattran DC, Miller JA, Scholey JW. 17β-estradiol modulates mechanical strain-induced MAPK activation in mesangial cells. J Biol Chem 277:9387-9397, 2002.

Chidambaram M, Duncan JA, Lai VS, Cattran DC, Floras JS, Scholey JW, Miller JA. Variations in the renin angiotensin system throughout the normal menstrual cycle. J Am Soc Nephrol 13:446-452, 2002.

Bartosik LP, Lajoie G, Sugar L, Cattran D. Predicting progression in IgA nephropathy.
Am J Kidney Dis 38:728-735, 2001.

Miller JA, Scholey JW. Angiotensin II type I receptor gene polymorphism and the response to hyperglycemia in early type 1 diabetes mellitus. Diabetes 40:1585-1589, 2000.

Future Directions

We intend to continue our multi-disciplinary approach, focusing on determination of the relationship between RAS genotypes, gender, and progression of renal disease; the mechanisms responsible for gender-specific responses to blockade of the RAS; gender differences in psychosocial and cultural variables and health promoting behaviors; and relationships between health promoting behaviors and progression of glomerular-based kidney disease. Ultimately we wish to design gender-specific interventions to maximize health in kidney disease. 

In the realm of diabetes, we intend to probe further the differences in the response to high glucose in diabetic patients segregated by genetic risk of nephropathy, ultimately to discover the mechanism that result in the initiation of nephropathy in 30% of diabetic patients, while 70% of patients remain protected from disease, despite equivalent glucose control.

INTEGRATIVE RENAL PHYSIOLOGY

Brief Description

We live in a new and exciting era in medicine because we have the opportunity to reinterpret traditionally accepted physiology at the molecular level. Hence there is a need for a broader and sounder reinterpretation of new discoveries from molecular medicine so that clinical diagnosis can be more accurate and therapeutic options be better designed. Therefore, the objectives of this program are to incorporate new molecular findings into the breadth of physiology and biochemistry and develop new concepts in regulation; and to illustrate that information must be interpreted outside of traditional subspecialty boundaries.

Principal Investigators

Recent Original Research Publications

Halperin ML, Kamel KS. Dynamic interactions between integrative physiology and molecular medicine: the key to understand the mechanism of action of aldosterone in the kidney. Can J Physiol Pharmacol 78:587-594, 2000.

Kamel KS, Cheema-Dhadli S, Halperin ML. Studies on the pathophysiology of the low urine pH in patients with uric acid stones. Kidney Int 61:988-994, 2002.

Cheema-Dhadli S, Halperin ML. Influence of hypernatraemia and urea excretion load on the ability to excrete a maximally hypertonic urine in the rat. J Physiol 541:929-936, 2002.

Cheema-Dhadli S, Lin S-H, Halperin ML. Mechanisms used to dispose of a progressively increasing alkali load in the rat.  Am J Physiol 282:F1049-F1055, 2002.

Kamel K, Mazer CD. Impact of NaHCO₃ therapy on contractile function and energy metabolism of the hypoxic myocardium. Crit Care Med 29: 344-350, 2001.

Future Directions

We shall continue current research thrusts with local and international collaborators

MEMBRANE BIOLOGY

Brief Description

The main objective of the CIHR Group in Membrane Biology is to understand the molecular basis of the function of a special group of membrane proteins that serve a critical role in regulating the molecular and ionic traffic across the cell surface. These membrane proteins are called transporters and channels. The specific objectives include study of different experimental model systems, including transporters, that regulate cell pH (anion transporter); drug transport and the development of resistance to cancer chemotherapy (P-glycoprotein); sugar transport across the intestinal epithelium; Na⁺ channels regulating the electrical conductivity of the heart; Ca⁺⁺ channels regulating insulin secretion in pancreatic cells; and Ca⁺⁺ channels regulating cell response to growth factor stimulation. We are interested in understanding these mechanisms at a very basic molecular level. Such knowledge would provide a basis for the development of new drugs targeted to domains on the transport and channel proteins that would allow modulation of their functional activity in normal and disease states.

Principal Investigators

Recent Original Research Publications

Vayro S, Silverman M. PKC regulates turnover rate of rabbit intestinal Na⁺-glucose transporter expressed in COS-7 cells. Am J Physiol 276:C1053-C1060, 1999.

Cho HC, Tsushima RG, Nguyen TTT, Guy RH, Backx PH. Two critical cysteine residues implicated in disulfide bond formation and proper folding of Kir2.1. Biochemistry 39:4649-4657, 2000.

Loo TW, Clarke DM. Defining the drug-binding site in the human multidrug resistance P-glycoprotein using a methanethiosulfonate analog of verapamil, MTS-verapamil. J Biol Chem 276:14972-14979, 2001.

Hua H, Goldberg HJ, Fantus IG, Whiteside CI. Role of specific PKC isozymes in endothelin-1 activation of glomerular cell ERK1/2 in normal and high glucose. Diabetes 50:2376-2383, 2001.

Zhao R, Reithmeier RAF. Expression and characterization of the anion transporter homologue YNL275w in Saccharomyces cerevisae. Am J Physiol 281:C33-C45, 2001.

Future Directions

At the time of our last grant renewal in 1999, the Group undertook a “marriage” of experiment and theory. We felt strongly that anticipated future advances in atomic level structural information for ion channels and transporters could be exploited using molecular modelling techniques to advance mechanistic understanding of transporters/channels. Accordingly, a Beowulf system has been purchased and is now functional in the Medical Sciences Building funded through the core budget of our Group. This facility is now supervised by a postdoctoral fellow and currently involves collaborative efforts between the Group and our associates at the University of Guelph. Our future plans are to increase efforts at obtaining structural information through the exploitation of 2-D electron microscopy (in collaboration), while simultaneously exploring new techniques to probe functional behaviour of channels/transporters at an atomic level (e.g. combined fluorescence and electrophysiology).

NOCTURNAL HEMODIALYSIS RESEARCH PROGRAM

Brief Description

Nocturnal hemodialysis (NHD) [8 hours/session, 6 times/week] is a novel form of renal replacement therapy, which has shown early clinical success. In a collaborative effort, we recently reported that NHD was associated with (1) enhanced uremia control, (2) normalization of blood pressure, (3) regression of left ventricular (LV) hypertrophy, (4) recovery of impaired LV systolic function, (5) improvement in nutritional parameters, (6) superior control of secondary hyperparathyroidism, and (7) improvement in total peripheral vascular resistance.

We aim to examine the impact of NHD on clinically relevant disease processes. We anticipate that documentation of marked reversal of major risk factors for adverse events should stimulate a fundamental reassessment of the mode and objectives of renal replacement therapy.

Principal Investigators

Recent Original Research Publications

Chan C, Floras J, Miller J, Richardson RMA, Pierratos A. Regression of left ventricular hypertrophy by nocturnal dialysis.  Kidney Int 61:2235-2239, 2002.

Chan C, Floras J, Miller J, Pierratos A. Improvement in left ventricular function by nocturnal hemodialysis. Nephrology, Dialysis and Transplantation 17:1518–1521, 2002.

Future Directions

Our major focus is the examination of NHD on human cardiovascular physiology. We will investigate the mechanisms underlying normalization of blood pressure in end-stage renal disease patients; correction of uremic related sleep apnea; changes in autonomic functions in relations to enhanced uremic clearance; and structure–function correlations in vascular physiology.