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Research Interests

Diabetes and congestive heart failure are diseases that have been associated with defects in the handling of salt and water by the kidney. Common in individuals with these disorders are elevated circulating levels of vasopressin, the peptide hormone that regulates renal water excretion. Circulating vasopressin plays a critical role in extra-cellular fluid expansion and development of hypertension, thus contributes to the pathogenesis of the disease.

      Vasopressin has clear long-term actions in the kidney, associated with regulatory processes at a transcriptional level as demonstrated by vasopressin-induced increases in aquaporin-2 transcription and translation. Circulating vasopressin also increases the concentrating capacity of the renal medulla by activating the counter current mechanism. The result is an increase in medullary osmotic stress that can directly activate renal cell signaling pathways and gene transcription. Thus specific effects of vasopressin on gene expression are not delineated from secondary alterations associated with this change in medullary osmolality.

      This is clinically important as patients with diabetes and heart failure have high levels of circulating vasopressin, but when treated with diuretics to reduce hypertension have decreased renal function and local osmolality.

       Our laboratory has been utilizing microarray technology to study the effects of vasopressin on gene expression in renal medullary cells. Using water restriction (WR) protocols to raise circulating vasopressin, we have identified vasopressin responsive genes in both wild type and AQP1 knockout mice. Due to the lack of a concentrating mechanism in the AQP1 knockout mice osmotically regulated transcripts should not be differentially expressed when vasopressin was increased in these mice. Our aim in applying microarray technology to the KO’s and normal mice was to rapidly identify vasopressin-responsive genes in common between the two physiological models. Our analysis revealed that 25 genes were significantly increased in both studies, i.e. increased in the water restricted wild type mice and increased in water restricted AQP1 KO animals. 15 genes were identified in common as significantly decreased following water restriction. We have focused our studies on two specific pathways that were identified as differentially expressed by in vivo increases in vasopressin: ER stress protein GRP78 and 3beta HSD steroid hormone enzymes

1)     We are investigating the role that GRP78 upregulation, by vasopressin, may play to precondition renal medullary cells from entering apoptosis following osmotic stress, and in the regulation of AQP2 trafficking to the membrane.

2)     Diabetes and Metabolic Syndrome : We study gender specific differences in the onset of metabolic syndrome and diabetes, focusing on diabetic kidney disease and renal function, and specifically the role that the steroid hormones testosterone and estrogen have on glucose impairment, insulin resistance, in addition to their effect on renal salt and water transport, and regulation of extracellular fluid balance

 

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Honours and Awards

2007 Lazaro Mandel Young Investigator Award, American Physiological Society
2006 APS New Investigator Award, Renal Section, American Physiological Society
2002 Research Recognition Award, American Physiological Society, Renal Section
1999 Award for Excellence in Renal Physiology (Hoechst Marion Roussel Postdoctoral Award) American Physiological Society

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Graduate Program Affiliations

Neuroscience

Physiological Sciences

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Publications

Fernandez SM, Keating AF, Christian PJ, Sen N, Hoying JB, Brooks HL, Hoyer PB. Apr 2008. Involvement of the KIT/KITL Signaling Pathway in 4-Vinylcyclohexene Diepoxide-Induced Ovarian Follicle Loss in Rats. Biol Reprod, e pub

Cai Q, McReynolds MR, Keck M, Greer KA, Hoying JB, Brooks HL. Dec 2007. Vasopressin receptor sub type 2 (V2R) activation increases cell proliferation in the renal medulla of AQP1 null mice. Am J Physiol Renal Physiol, 293:F1858-64

Pysher MD, Sollome JJ, Regan S, Cardinal TR, Hoying JB, Brooks HL, Vaillancourt RR. Oct 2007. Increased hexokinase II expression in the renal glomerulus of mice in response to arsenic. Toxicol Appl Pharmacol, 224:39-48

Keck M, Romero-Aleshire MJ, Cai Q, Hoyer PB, Brooks HL. Jul 2007. Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause. Am J Physiol Renal Physiol, 293:F193-F199

Kim D, Wang M, Cai, Q, Brooks, HL, Dressler GR. May 2007. Pax transactivation-domain interacting protein is required for urine concentration and osmotolerance in collecting duct epithelia. Journal of the American Society of Nephrology, 18 (5):1458-65

Chakraborty A, Brooks HL, Zhang P, Smith W, McReynolds M, Hoying J, Bick RJ, Truong L, Poindexter B, Lan H, Elbjeirami W, Sheikh-Hamad D. Feb 2007. Stanniocalcin-1 regulates endothelial gene expression and modulates trans-endothelial migration of leukocytes. Am J Physiol Renal Physiol., 292:F895-904

Hawkins BT Lundeen TF Norwood KM Brooks HL Egleton RD. Jan 2007. Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases. Diabetologia, 50:202-11

Carmosino M, Brooks HL, Cai Q, Davis LS, Opalenik S, Hao CM, Breyer MD. Jan 2007. Axial heterogeneity of Vasopressin receptor subtypes along the human and mouse collecting duct. Am J Physiol Renal Physiol, 292:F351-F360

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