Impaired renal hemodynamics and glomerular hyperfiltration contribute to hypertension-induced renal injury

Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulatio...

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Published in:American journal of physiology. Renal physiology 2020-10, Vol.319 (4), p.F624-F635
Main Authors: Fan, Letao, Gao, Wenjun, Nguyen, Bond V, Jefferson, Joshua R, Liu, Yedan, Fan, Fan, Roman, Richard J
Format: Article
Language:English
Subjects:
Adducin
Animals
Arterioles
Arterioles - metabolism
Arterioles - physiopathology
Blood flow
Blood Pressure
Calmodulin-Binding Proteins - genetics
Calmodulin-Binding Proteins - metabolism
Desoxycorticosterone Acetate
Disease Models, Animal
Disease Progression
Glomerular Filtration Rate
Hemodynamics
Homeostasis
Hypertension
Hypertension - complications
Hypertension - genetics
Hypertension - metabolism
Hypertension - physiopathology
Kidney diseases
Kidney Glomerulus - blood supply
Male
Muscle Development
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - physiopathology
Proteinuria
Proteinuria - etiology
Proteinuria - genetics
Proteinuria - metabolism
Proteinuria - physiopathology
Rats, Transgenic
Renal Circulation
Renal Insufficiency, Chronic - etiology
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - metabolism
Renal Insufficiency, Chronic - physiopathology
Rodents
Sensory neurons
Sodium Chloride, Dietary
Vascular Remodeling
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Summary:Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1 congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1 KO ( KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in KO rats. The degree of renal injury was greater in KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive KO rats.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.00239.2020