Grant: $85,608 - National Institutes of Health - Aug. 31, 2009
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Award Description: Despite substantial progress several fundamental issues of hypertensive renal damage remain unresolved. (1) The term 'BP load' is still used genetically due to the complexity of the BP phenotype because of its fundamental lability and oscillating phenotype and because the relative pathogenic importance of individual BP parameters (components) remains poorly defined. (2) Likewise, the real time renal transmission of the fluctuating BP must be a dynamic process, but methods to assess such transmission in the conscious unanaesthetized state remain to be developed and validated. (3) Although an impairment of protective renal autoregulation (AR) is recognized to play a central role in the enhanced BP transmission and the increased susceptibility of chronic kidney disease patients to hypertensive induced renal damage (HERD), the responsible mechanisms remain obscure. Specific Aim 1 is addressed to the question - - what is the pathogenetically relevant definition of the 'aggregate BP load' for the renal vascular bed. We will test the hypothesis that a more precise quantitation of 'BP load' may be achieved by a biophysical estimation of the BP energy and its individual components for correlation with HIRD. This will be performed in rats with remnant kidneys because of their enhanced susceptibility to HIRD. Suboptimal antihypertensive therapy will be used to increase the natural variability of the 'BP load' components. Multivariant analysis will be used to examine the separate or combined contribution of the individual 'BP load' components to renal damage. Specific Aim 2 is addressed to the assessment of dynamic BP transmission in conscious rats. Our studies have shown that in contrast to the currently used but poorly predictive parameters, transfer function analysis of the admittance gain at the heart beat frequency and the magnitude of the myogenic resonance peak might provide better indices. The validity of these proposed parameters will be examined by their correlations and/or correspondence with the magnitude and/or kinetics of the AR response during step changes in BP in several models in which such step responses have shown excellent correlations with susceptibility to HIRD. Specific Aim 3 will address the mechanisms responsible for the impaired renal AR in afferent arterioles isolated from remnant kidneys. Our preliminary results have suggested that the inward rectifier potassium channel (Kir) that plays a major role in the pressure induce depolarization and myogenic responses and its function, is altered in remnant kidneys. Further characterization of the altered signal transduction mechanisms will be performed in similarly isolated afferent arterioles and myocytes using techniques that are well established in Dr. Loutzenhiser's laboratory. We believe that the collective expertise of the investigative team is uniquely equipped to address these fundamental questions in the pathogenesis of HIRD.
Project Description: The overall purpose of the award was to enable the hiring of a new research associate, Dr. Aaron Polichnowski to facilitate and expedite the performance of dynamic autoregulatory studies in conscious rats as described under specific aim 2 of Dr. Bidani?s grant ?Dynamics of BP Transmission and Hypertensive Renal Injury? (5R01DK40426-17). Such studies have been initiated and it is envisioned that the hiring of Dr. Polichnowski will accelerate the tempo and pace of the investigations to allow them to be completed a year ahead of schedule.
Jobs Summary: New Research Associate, Dr. Aaron Polichnowski (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 31, 2009. Help expand these official descriptions using the wiki below.