Long-term constancy of body salt content is a requirement for maintenance of body fluid volumes and arterial blood pressure, and this constancy is achieved by the renal excretion of Na in an amount that matches Na intake. Urinary Na excretion results from the filtration of plasma in the renal glomeruli and subsequent reabsorption of most of the filtered Na along the renal tubules. Defective absorption of Na and water is the cause for a number of diseases including Bartter's syndrome and pseudohypoaldosteronism. In several instances, however, symptomatic salt losses do not occur despite defective absorption of Na suggesting the operation of compensatory mechanisms. Studies in NHE3 and AQP1 knockout mice, transport proteins in the proximal tubule where 60-70% of the filtered Na is normally absorbed, have shown that these mice maintain a normal salt balance and that a reduction in glomerular filtration rate is the main compensatory mechanism preventing salt losses. The reduction in GFR is caused by a signal transmitted from the distal tubule to the glomerular arterioles across the juxtaglomerular apparatus. This mechanism, called the tubuloglomerular feedback (TGF) mechanism, is rendered inoperative by inhibition of the Na,K,2Cl-cotransporter in the loop of Henle (NKCC2). NKCC2 mutations such as in Bartter's syndrome are therefore not compensated by GFR reductions. NKCC2 mutations also result in overproduction of prostaglandins which contribute to the salt loss, a notion supported by the reduced natriuretic response to NKCC2 inhibition in cyclooxygenase knockout mice. Using micropuncture techniques in mice with a knockout of the epithelial nitric oxide synthase (bNOS) gene we identified formation of NO in the juxtaglomerular apparatus as an important regulating factor in the TGF mechanism. NO produced by endothelial NO synthase (eNOS) is mainly responsible for the low basal renal vascular resistance since renal blood flow and GFR are greatly reduced in eNOS knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK043408-01
Application #
6421449
Study Section
(MDB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kim, S M; Mizel, D; Qin, Y et al. (2015) Blood pressure, heart rate and tubuloglomerular feedback in A1AR-deficient mice with different genetic backgrounds. Acta Physiol (Oxf) 213:259-67
Schnermann, Jurgen; Huang, Yuning; Mizel, Diane (2013) Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. Am J Physiol Renal Physiol 305:F1352-64
Doi, Kent; Yuen, Peter S T; Eisner, Christoph et al. (2009) Reduced production of creatinine limits its use as marker of kidney injury in sepsis. J Am Soc Nephrol 20:1217-21
Kim, Soo Mi; Chen, Limeng; Mizel, Diane et al. (2007) Low plasma renin and reduced renin secretory responses to acute stimuli in conscious COX-2-deficient mice. Am J Physiol Renal Physiol 292:F415-22
Oppermann, Mona; Mizel, Diane; Kim, Soo Mi et al. (2007) Renal function in mice with targeted disruption of the A isoform of the Na-K-2Cl co-transporter. J Am Soc Nephrol 18:440-8
Oppermann, Mona; Hansen, Pernille B; Castrop, Hayo et al. (2007) Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice. Am J Physiol Renal Physiol 293:F279-87
Kim, Soo Mi; Chen, Limeng; Faulhaber-Walter, Robert et al. (2007) Regulation of renin secretion and expression in mice deficient in beta1- and beta2-adrenergic receptors. Hypertension 50:103-9
Chen, Limeng; Kim, Soo Mi; Oppermann, Mona et al. (2007) Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsalpha in juxtaglomerular cells. Am J Physiol Renal Physiol 292:F27-37
Paliege, A; Pasumarthy, A; Parsumathy, A et al. (2006) Effect of apocynin treatment on renal expression of COX-2, NOS1, and renin in Wistar-Kyoto and spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 290:R694-700
Castrop, H; Oppermann, M; Weiss, Y et al. (2006) Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene. Physiol Genomics 25:277-85

Showing the most recent 10 out of 53 publications