On determinants of glomerular filtration rate after inhibition of proximal tubular reabsorption

Leyssac, P. P.; Karlsen, Finn Michael; Holstein‐Rathlou, N. H.; Skøtt, Ole

doi:10.1152/ajpregu.1994.266.5.r1544

Cited by 28 publications

(40 citation statements)

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“…Therefore, it is likely that the mechanisms behind the fall of GFR in states of proximal malabsorption are multifactorial. There is evidence that TGF-independent reductions of GFR could result from increases in tubular pressure, reductions in renal blood flow, and from the complex consequences of extracellular volume depletion (21,24). Elevated hematocrit values in mutant mice in the micropuncture phase suggest the existence of volume depletion in the present study.…”

Section: Previous Observations In Cldn2supporting

confidence: 47%

Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1

Schnermann

Huang

Mizel

2013

American Journal of Physiology-Renal Physiology

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Schnermann J, Huang Y, Mizel D. Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. Am J Physiol Renal Physiol 305: F1352-F1364, 2013. First published September 18, 2013 doi:10.1152/ajprenal.00342.2013.-Deletions of claudin-2 (Cldn2) and aquaporin1 (AQP1) reduce proximal fluid reabsorption (PFR) by about 30% and 50%, respectively. Experiments were done to replicate these observations and to determine in AQP1/claudin-2 double knockout mice (DKO) if the effects of deletions of these established water pores are additive. PFR was determined in inactin/ketamine-anesthetized mice by free-flow micropuncture using single-nephron I 125 -iothalamate (io) clearance. Animal means of PFR [% of glomerular filtration rate (GFR)] derived from TF/P iothalamate ratios in 12 mice in each of four groups [wild type (WT), Cldn2 Ϫ/Ϫ , AQP1 Ϫ/Ϫ , and DKO) were 45.8 Ϯ 0.85 (51 tubules), 35.4 Ϯ 1 (54 tubules; P Ͻ 0.01 vs. WT), 36.8 Ϯ 1 (63 tubules; P Ͻ 0.05 vs. WT), and 33.9 Ϯ 1.4 (69 tubules; P Ͻ 0.01 vs. WT). Kidney and single-nephron GFRs (SNGFR) were significantly reduced in all mutant strains. The direct relationship between PFR and SNGFR was maintained in mutant mice, but the slope of this relationship was reduced in the absence of Cldn2 and/or AQP1. Transtubular osmotic pressure differences were not different between WT and Cldn2 Ϫ/Ϫ mice, but markedly increased in DKO. In conclusion, the deletion of Cldn2, AQP1, or of both Cldn2 and AQP1 reduces PFR by 22.7%, 19.6%, and 26%, respectively. Our data are consistent with an up to 25% paracellular contribution to PFR. The reduced osmotic water permeability caused by absence of AQP1 augments luminal hypotonicity. Aided by a fall in filtered load, the capacity of non-AQP1-dependent transcellular reabsorption is sufficient to maintain PFR without AQP1 and claudin-2 at 75% of control. micropuncture; iothalamate; tubular fluid osmolarity; paracellular; transcellular SEEMINGLY EXCESSIVE AMOUNTS of water and solutes crossing the glomerular filtration barrier are reduced by the renal tubular epithelium to the small quantities that must be excreted in the urine to achieve fluid volume and blood pressure homeostasis. All segments of the nephron participate in this vital task of fluid and solute retrieval, but the greatest reabsorptive burden is carried by the proximal tubules of the nephron. The architecture of the proximal tubular epithelium suggests two principal pathways of transtubular movement: permeation through the epithelial cells (transcellular) or permeation between the epithelial cells (paracellular). There is agreement that solutes and water use both routes to gain access to the blood, but estimates of the magnitudes of transcellular vs. paracellular absorption rates have been difficult to establish. Nevertheless, measurements of transtubular and transmembrane fluxes by micropuncture, microperfusion, and membrane fractionation together with the subsequent identification and manipulation of the major solute transport proteins...

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Section: Previous Observations In Cldn2supporting

confidence: 47%

Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1

Schnermann

Huang

Mizel

2013

American Journal of Physiology-Renal Physiology

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“…3. The estimated value of P GC corresponds well to values measured directly in the glomerular capillary (20,21).…”

Section: Glomerular Capillary Pressure R Pre and R Postsupporting

confidence: 82%

ANG II-induced downregulation of RBF after a prolonged reduction of renal perfusion pressure is due to pre- and postglomerular constriction

Sørensen¹,

Leyssac²,

Salomonsson³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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-Rathlou. ANG II-induced downregulation of RBF after a prolonged reduction of renal perfusion pressure is due to pre-and postglomerular constriction. Am J Physiol Regul Integr Comp Physiol 286: R865-R873, 2004. First published January 8, 2004 10.1152/ajpregu.00424.2003.-Previous experiments from our laboratory showed that longer-lasting reductions in renal perfusion pressure (RPP) are associated with a gradual decrease in renal blood flow (RBF) that can be abolished by clamping plasma ANG II concentration ([ANG II]). The aim of the present study was to investigate the mechanisms behind the RBF downregulation in halothane-anesthetized Sprague-Dawley rats during a 30-min reduction in RPP to 88 mmHg. During the 30 min of reduced RPP we also measured glomerular filtration rate (GFR), proximal tubular pressure (P prox), and proximal tubular flow rate (QLP). Early distal tubular fluid conductivity was measured as an estimate of early distal [NaCl] ([NaCl] ED), and changes in plasma renin concentration (PRC) over time were measured. During 30 min of reduced RPP, RBF decreased gradually from 6.5 Ϯ 0.3 to 6.0 Ϯ 0.3 ml/min after 5 min (NS) to 5.2 Ϯ 0.2 ml/min after 30 min (P Ͻ 0.05). This decrease occurred in parallel with a gradual increase in PRC from 38.2 Ϯ 11.0 ϫ 10 Ϫ5 to 87.1 Ϯ 25.1 ϫ 10 Ϫ5 Goldblatt units (GU)/ml after 5 min (P Ͻ 0.05) to 158.5 Ϯ 42.9 ϫ 10 Ϫ5 GU/ml after 30 min (P Ͻ 0.01). GFR, P prox, and [NaCl]ED all decreased significantly after 5 min and remained low. Estimates of pre-and postglomerular resistances showed that the autoregulatory mechanisms initially dilated preglomerular vessels to maintain RBF and GFR. However, after 30 min of reduced RPP, both pre-and postglomerular resistance had increased. We conclude that the decrease in RBF over time is caused by increases in both pre-and postglomerular resistance due to rising plasma renin and ANG II concentrations. renal vascular resistance; autoregulation; glomerular filtration rate THE MYOGENIC RESPONSE and the tubuloglomerular feedback (TGF) mechanism autoregulate renal blood flow (RBF) and glomerular filtration rate (GFR) when acute changes in renal perfusion pressure (RPP) occur (26,36). Autoregulation ensures that the kidney accurately can control salt and water excretion and thereby maintain the extracellular fluid volume by separating kidney function from acute fluctuations in blood pressure.A previous study from our laboratory showed that a longerlasting decrease in RPP is associated with a decrease in RBF that gradually develops a few minutes after the pressure reduction (38). This is also the case when the decrease in RPP is within the limits of autoregulation. This we refer to as regulation of RBF. Because this downregulation of RBF could be completely abolished by clamping the plasma ANG II concentration ([ANG II]), we hypothesized that the decrease in RBF was dependent on an increase in local and plasma [ANG II].The mechanism behind this downregulation of RBF is not clear. A direct effect of ANG II on the renal vessels is possible. As RPP ...

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“…Changes in luminal flow are the result of variations in glomerular filtration rate (29,49), tubuloglomerular feedback (17), and fluid absorption along the nephron (29,50). Mechanical constriction of the renal pelvis can halt and even reverse flow (8,44).…”

Section: Discussionmentioning

confidence: 99%

“…Acutely it changes due to glomerular filtration rate (29), tubuloglomerular feedback (17,28), peristalsis of the renal pelvis (8,44), and fluid reabsorption (29,50). Hypertension (4,6), volume status (3,42), and diabetes (40) can change luminal flow chronically.…”

mentioning

confidence: 99%

Endogenous flow-induced superoxide stimulates Na/H exchange activity via PKC in thick ascending limbs

Hong

Garvin

2014

American Journal of Physiology-Renal Physiology

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Hong NJ, Garvin JL. Endogenous flow-induced superoxide stimulates Na/H exchange activity via PKC in thick ascending limbs. Am J Physiol Renal Physiol 307: F800 -F805, 2014. First published July 30, 2014 doi:10.1152/ajprenal.00260.2014.-Luminal flow stimulates Na reabsorption along the nephron and activates protein kinase C (PKC) which enhances endogenous superoxide (O 2 Ϫ ) production by thick ascending limbs (TALs). Exogenously-added O 2 Ϫ augments TAL Na reabsorption, a process also dependent on PKC. Luminal Na/H exchange (NHE) mediates NaHCO 3 reabsorption. However, whether flow-stimulated, endogenously-produced O 2 Ϫ enhances luminal NHE activity and the signaling pathway involved are unclear. We hypothesized that flow-induced production of endogenous O 2 Ϫ stimulates luminal NHE activity via PKC in TALs. Intracellular pH recovery was measured as an indicator of NHE activity in isolated, perfused rat TALs. Increasing luminal flow from 5 to 20 nl/min enhanced total NHE activity from 0.104 Ϯ 0.031 to 0.167 Ϯ 0.036 pH U/min, 81%. The O 2 Ϫ scavenger tempol decreased total NHE activity by 0.066 Ϯ 0.011 pH U/min at 20 nl/min but had no significant effect at 5 nl/min. With the NHE inhibitor EIPA in the bath to block basolateral NHE, tempol reduced flow-enhanced luminal NHE activity by 0.029 Ϯ 0.010 pH U/min, 30%. When experiments were repeated with staurosporine, a nonselective PKC inhibitor, tempol had no effect. Because PKC could mediate both induction of O 2 Ϫ by flow and the effect of O 2 Ϫ on luminal NHE activity, we used hypoxanthine/ xanthine oxidase to elevate O 2 Ϫ . Hypoxanthine/xanthine oxidase increased luminal NHE activity by 0.099 Ϯ 0.020 pH U/min, 137%. Staurosporine and the PKC␣/␤1-specific inhibitor Gö6976 blunted this effect. We conclude that flow-induced O 2 Ϫ stimulates luminal NHE activity in TALs via PKC␣/␤1. This accounts for part of flow-stimulated bicarbonate reabsorption by TALs. reactive oxygen species; luminal flow; protein kinases; sodium/hydrogen exchange LUMINAL FLOW IN THE NEPHRON is highly variable. Acutely it changes due to glomerular filtration rate (29), tubuloglomerular feedback (17, 28), peristalsis of the renal pelvis (8, 44), and fluid reabsorption (29, 50). Hypertension (4, 6), volume status (3, 42), and diabetes (40) can change luminal flow chronically. Increases in luminal flow enhance Na reabsorption in the proximal tubule (7, 46), thick ascending limb of the loop of Henle (39), and cortical collecting duct (10, 43). However, the mechanisms involved are not fully understood.The thick ascending limb is important in salt, water, and acid/base homeostasis (15,16,35). Na is reabsorbed by thick ascending limbs as NaCl and Na bicarbonate via Na-K-2Cl cotransport (35) and Na/H exchange (NHE) (15, 16), respectively. Luminal flow in this segment may be as high as 20 nl/min during conditions of diuresis (4, 30, 42) and may stop due to peristalsis of the renal pelvis (8,42,44 enhances Na reabsorption in thick ascending limbs. We showed that exogenously-added O 2 Ϫ stimulates net N...

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On determinants of glomerular filtration rate after inhibition of proximal tubular reabsorption

Cited by 28 publications

References 0 publications

Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1

Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1

ANG II-induced downregulation of RBF after a prolonged reduction of renal perfusion pressure is due to pre- and postglomerular constriction

Endogenous flow-induced superoxide stimulates Na/H exchange activity via PKC in thick ascending limbs

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