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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040426-18
Application #
7786242
Study Section
Special Emphasis Panel (ZRG1-RUS-A (03))
Program Officer
Ketchum, Christian J
Project Start
1990-02-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
18
Fiscal Year
2010
Total Cost
$242,143
Indirect Cost
Name
Chicago Assn for Research & Education in Sci
Department
Type
DUNS #
187174339
City
Hines
State
IL
Country
United States
Zip Code
60141
Griffin, Karen A (2017) Hypertensive Kidney Injury and the Progression of Chronic Kidney Disease. Hypertension 70:687-694
Bidani, Anil K; Griffin, Karen A (2015) Basic science: hypertensive target organ damage. J Am Soc Hypertens 9:235-7; quiz 238
Polichnowski, Aaron J; Licea-Vargas, Hector; Picken, Maria et al. (2015) Glomerulosclerosis in the diet-induced obesity model correlates with sensitivity to nitric oxide inhibition but not glomerular hyperfiltration or hypertrophy. Am J Physiol Renal Physiol 309:F791-9
Polichnowski, Aaron J; Griffin, Karen A; Picken, Maria M et al. (2015) Hemodynamic basis for the limited renal injury in rats with angiotensin II-induced hypertension. Am J Physiol Renal Physiol 308:F252-60
Polichnowski, Aaron J; Lan, Rongpei; Geng, Hui et al. (2014) Severe renal mass reduction impairs recovery and promotes fibrosis after AKI. J Am Soc Nephrol 25:1496-507
Griffin, Karen A; Polichnowski, Aaron; Litbarg, Natalia et al. (2014) Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model. Hypertension 64:801-7
Bidani, Anil K; Polichnowski, Aaron J; Loutzenhiser, Rodger et al. (2013) Renal microvascular dysfunction, hypertension and CKD progression. Curr Opin Nephrol Hypertens 22:1-9
Polichnowski, Aaron J; Griffin, Karen A; Long, Jianrui et al. (2013) Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats. Am J Physiol Renal Physiol 305:F1074-84
Griffin, Karen; Polichnowski, Aaron; Licea-Vargas, Hector et al. (2012) Large BP-dependent and -independent differences in susceptibility to nephropathy after nitric oxide inhibition in Sprague-Dawley rats from two major suppliers. Am J Physiol Renal Physiol 302:F173-82
Lan, Rongpei; Geng, Hui; Polichnowski, Aaron J et al. (2012) PTEN loss defines a TGF-?-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis. Am J Physiol Renal Physiol 302:F1210-23

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