The macula densa is worth its salt

Schnermann, Jürgen; Briggs, Josie P.

doi:10.1172/jci8539

Cited by 34 publications

(33 citation statements)

References 18 publications

(18 reference statements)

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“…The selected flow rates for the isolated, microperfused tubules reflected the end proximal physiologic range of 5-30 nl/min. 25 Our data support the concept that the cell may adjust AQP1 membrane density within the short term to augment its transepithelial water movement, because at high-flow rate, AQP1 surface expression, as established by immunogold labeling, was increased apically at the BBM as well as basolaterally after 15 minutes. This concept was indirectly supported by models in which a downregulated AQP1 surface expression coincided with reduced GFR.…”

Section: Discussionsupporting

confidence: 85%

Short-Term Functional Adaptation of Aquaporin-1 Surface Expression in the Proximal Tubule, a Component of Glomerulotubular Balance

Pohl

Shan

Petsch

et al. 2015

Journal of the American Society of Nephrology

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Transepithelial water flow across the renal proximal tubule is mediated predominantly by aquaporin-1 (AQP1). Along this nephron segment, luminal delivery and transepithelial reabsorption are directly coupled, a phenomenon called glomerulotubular balance. We hypothesized that the surface expression of AQP1 is regulated by fluid shear stress, contributing to this effect. Consistent with this finding, we found that the abundance of AQP1 in brush border apical and basolateral membranes was augmented .2-fold by increasing luminal perfusion rates in isolated, microperfused proximal tubules for 15 minutes. Mouse kidneys with diminished endocytosis caused by a conditional deletion of megalin or the chloride channel ClC-5 had constitutively enhanced AQP1 abundance in the proximal tubule brush border membrane. In AQP1-transfected, cultured proximal tubule cells, fluid shear stress or the addition of cyclic nucleotides enhanced AQP1 surface expression and concomitantly diminished its ubiquitination. These effects were also associated with an elevated osmotic water permeability. In sum, we have shown that luminal surface expression of AQP1 in the proximal tubule brush border membrane is regulated in response to flow. Cellular trafficking, endocytosis, an intact endosomal compartment, and controlled protein stability are the likely prerequisites for AQP1 activation by enhanced tubular fluid shear stress, serving to maintain glomerulotubular balance.

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Section: Discussionsupporting

confidence: 85%

Short-Term Functional Adaptation of Aquaporin-1 Surface Expression in the Proximal Tubule, a Component of Glomerulotubular Balance

Pohl

Shan

Petsch

et al. 2015

Journal of the American Society of Nephrology

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“…We do not know whether the high hematocrit is solely because of a decrease in plasma volume or whether excessive production of erythropoietin also is involved as is in the case of some human Bartter's syndrome patients (5). In the normal kidney, when a low Cl ion concentration is sensed by the macula densa, two major changes occur: glomerular filtration is increased, and renin is released from the adjacent juxtaglomerular cells (17,27,34). All our data are compatible with this Cl-sensing mechanism being disabled in the NKCC2Ϫ͞Ϫ mice, so that the macula densa cells transmit the signal that normally results from a very low Cl ion concentration in the luminal fluid.…”

Section: Distribution Of Reninsupporting

confidence: 70%

“…The cause of the extremely high plasma renin concentration is an increase in the proportion of vascular smooth muscle cells, pericytes, and mesangial cells that produce renin (26). This increase most likely occurs because the macula densa cells transduce a signal falsely indicating a very low amount of chloride in the lumen (17,27), and because dehydration and volume depletion (1,28) diminish the stretch of the arterioles.…”

Section: Distribution Of Reninmentioning

confidence: 99%

Uncompensated polyuria in a mouse model of Bartter's syndrome

Takahashi

Cherñavvsky

Gomez

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

229

172

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We have used homologous recombination to disrupt the mouse gene coding for the NaK2Cl cotransporter (NKCC2) expressed in kidney epithelial cells of the thick ascending limb and macula densa. This gene is one of several that when mutated causes Bartter's syndrome in humans, a syndrome characterized by severe polyuria and electrolyte imbalance. Homozygous NKCC2؊͞؊ pups were born in expected numbers and appeared normal. However, by day 1 they showed signs of extracellular volume depletion (hematocrit 51%; wild type 37%). They subsequently failed to thrive. By day 7, they were small and markedly dehydrated and exhibited renal insufficiency, high plasma potassium, metabolic acidosis, hydronephrosis of varying severity, and high plasma renin concentrations. None survived to weaning. Treatment of ؊͞؊ pups with indomethacin from day 1 prevented growth retardation and 10% treated for 3 weeks survived, although as adults they exhibited severe polyuria (10 ml͞day), extreme hydronephrosis, low plasma potassium, high blood pH, hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacinrescued ؊͞؊ adults except that hydronephrosis was mild. The polyuria, hypercalciuria, and proteinuria of the ؊͞؊ adults and furosemide-treated wild-type mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, and further indomethacin. Thus absence of NKCC2 in the mouse causes polyuria that is not compensated elsewhere in the nephron. The NKCC2 mutant animals should be valuable for uncovering new pathophysiologic and therapeutic aspects of genetic disturbances in water and electrolyte recovery by the kidney.gene targeting ͉ NaK2Cl cotransporter ͉ nonsteroidal anti-inflammatory drug ͉ hydronephrosis

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“…[4][5][6][7][8] The role and mechanisms of tubuloglomerular feedback responsiveness in control of SNGFR and renal hemodynamics have been extensively studied and well established. [4][5][6][7][8][9][10][11][12][13][14] However, it should be noted that the majority of the previous studies were largely focused on acute responses. The long-term significance of tubuloglomerular feedback, especially in the chronic regulation of renal hemodynamics, sodium and water balance, and BP, remains mostly hypothetical on the basis of extrapolation of the results from acute experiments.…”

Section: Discussionmentioning

confidence: 99%

“…This negative feedback loop prevents acute fluctuations in Af-Art pressure from altering SNGFR and stabilizes NaCl delivery to the distal nephron. [4][5][6][7][8][9][10][11][12][13][14] We recently reported that the macula densa expresses a-, b-, and g-splice variants of nitric oxide synthase 1 (NOS1) and that expression of NOS1b increases in animals fed a high-salt diet. 15 Therefore, NOS1b may be a salt-sensitive isoform in the macula densa that modulates tubuloglomerular feedback response, promotes sodium excretion, and protects against the development of salt-sensitive hypertension.…”

mentioning

confidence: 99%

Macula Densa Nitric Oxide Synthase 1β Protects against Salt-Sensitive Hypertension

Liu

Jin

Stec

et al. 2015

JASN

100

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Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses a-, b-, and g-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1b expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1b expression in the macula densa affects sodium excretion and saltsensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1b mRNA and protein were 30-and five-fold higher, respectively, than those of NOS1a in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1a-knockout (NOS1aKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P,0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P,0.01) fed a high-salt diet. These results indicate that NOS1b is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.

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The macula densa is worth its salt

Cited by 34 publications

References 18 publications

Short-Term Functional Adaptation of Aquaporin-1 Surface Expression in the Proximal Tubule, a Component of Glomerulotubular Balance

Short-Term Functional Adaptation of Aquaporin-1 Surface Expression in the Proximal Tubule, a Component of Glomerulotubular Balance

Uncompensated polyuria in a mouse model of Bartter's syndrome

Macula Densa Nitric Oxide Synthase 1β Protects against Salt-Sensitive Hypertension

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