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Renal Handling of Proteins and Polypeptides

Thomas Maack

10.1002/cphy.cp080244

Source: Supplement 25: Handbook of Physiology, Renal Physiology

Originally published: 1992

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Endocytosis
1.1 Fluid‐Phase Endocytosis
1.2 Adsorptive Endocytosis
1.3 Nature and Functions of Endosomes
1.4 Lysosomal Hydrolysis of Absorbed Proteins
2 Renal Uptake and Extraction of Proteins and Polypeptides
2.1 Renal Accumulation of Administered Proteins
2.2 Nephron and Intracellular Localization of Protein Uptake
2.3 Renal Extraction and Turnover of Circulating Proteins
3 Filtration of Proteins
4 Tubular Absorption of Filtered Proteins
4.1 Effect of Inhibitors
4.2 Effect of Protein Charge
4.3 Competition for Tubular Uptake
4.4 Selective Constraint Model
4.5 Tubular Absorption of Albumin
4.6 Urinary Proteins and Proteinurias
5 Intracellular Transport and Hydrolysis of Absorbed Proteins
5.1 Vesicular Transport
5.2 Lysosomal Hydrolysis
5.3 Influence of Lysosomal pH on Renal Hydrolysis of Absorbed Proteins
5.4 Renal Hydrolysis of Absorbed Albumin
5.5 Deposition of Absorbed Protein within Renal Cells
6 Renal Handling of Specific Polypeptide Hormones
6.1 Insulin and Related Peptides
6.2 Glucagon and Related Peptides
6.3 Parathyroid Hormone
6.4 Atrial Natriuretic Factor
7 Conclusions
Figure 1. Figure 1.

Schematic representation of endocytosis and intracellular transport of proteins. CP, coated pit; CV, coated vesicle; MVE, multivesicular endosome; MVB, multivesicular body; R, receptor. See text for description.

From Wall and Maack 270
Figure 2. Figure 2.

Renal accumulation of low‐molecular‐weight proteins (LMWP) in isolated perfused rat kidney in control conditions, or in presence of metabolic inhibitors, or in absence of filtration. rLZM, rat lysozyme; INS, insulin; rGH, rat growth hormone; bPTH, bovine parathyroid hormone; IAA, iodoacetate (10 mM); KCN, potassium cyanide (3 mM). LMWP are markedly accumulated in renal tissue, a phenomenon practically abolished by metabolic inhibitors or when kidneys are perfused in nonfiltering mode.

From Maack et al. 138
Figure 3. Figure 3.

Schematic representation of factors affecting filtration of macromolecules. Glomerular–capillary interface is represented with hypothetical pores of fixed dimensions, where Δx is pore length and A is pore diameter. Cp, protein concentration in glomerular capillary plasma; CF, protein concentration in glomerular filtrate; GFR, glomerular filtration rate; a, molecular dimension hindrance; b, steric hindrance; C, viscous drag; d, electrical hindrance, e, protein‐protein binding. Proteins with dimensions larger than the size of “pores” or bound to larger plasma proteins are not filtered (a, e). Proteins in which at least one diameter is smaller than diameter of “pores” are restricted in passage to glomerular filtrate by steric hindrance, viscous drag, and electrical hindrance (b, c, d). Electrical hindrance retards passage of negatively charged proteins and favors passage of positively charged proteins to glomerular filtrate. Steric hindrance, viscous drag, and electrical hindrance are more pronounced for intermediate‐sized proteins and have relatively little influence on filtration of low‐molecular‐weight proteins (for detailed quantitative description of glomerular permselectivity to macromolecules and proteins, see refs. 16,21,45,121,122,189,190,222).

From Maack and Sherman 143
Figure 4. Figure 4.

Tubular absorption of proteins after injection into surface proximal and distal tubules of rat. Results given as percentages of radioactivity recovered in ureteral urine after injection of [131I]iothalamate (nonreabsorbable substance), [131I]human serum albumin (RISA), and [131I]pork insulin. Proteins are extensively absorbed when injected into early proximal but not late proximal or early distal tubules. Absorption of insulin is proportionately greater than that of albumin and is not saturated over range of concentrations shown.

From Cortney et al. 40
Figure 5. Figure 5.

Renal titration curves of lysozyme (LZM, top) and cytochrome c (CYT C, bottom) in isolated perfused rat kidney. U, urinary concentration of CYT c; V, urine flow rate; P, plasma concentration of CYT c. Tm, tubular maximum of absorption; KPL, filtered loads of protein that lead to half‐maximal absorption (dashed lines); GFR, glomerular filtration rate; GSC, glomerular sieving coefficient of CYT c. See text for description.

From Sumpio and Maack 257
Figure 6. Figure 6.

Effect of iodoacetate (IAA) on albumin absorption (JALB) and fluid reabsorption (Jv) in isolated perfused proximal convoluted tubules of rabbit. Results expressed as percentages of control values obtained before addition of IAA (4 mM) to bathing solution. IAA practically abolished JALB, and inhibited JV to a smaller extent than JALB.

From Park and Maack 193
Figure 7. Figure 7.

Competition for tubular uptake between lysozyme and cytochrome c in isolated perfused rat kidney. Filtered load of cytochrome c was constant at approximately 1 μg/min; lysozyme loads increased stepwise to values indicated on abscissa.

From Sumpio and Maack 257
Figure 8. Figure 8.

Schematic representation of selective constraint model for tubular absorption of proteins. See text for description.

From Sumpio and Maack 257
Figure 9. Figure 9.

Absorption and fate of albumin in isolated perfused proximal convoluted tubules of rabbit. Tubules were perfused for approximately 1 h with perfusion fluid containing 0.03 mg/ml of [3H3C]albumin. A: 3H radioactivity absorbed from tubular lumen appears in bathing solution; only small proportion remains in tubular cells at end of perfusion. Rate of efflux of radioactivity from lumen corresponds to rate of albumin absorption of approximately 10% of perfused load of albumin per millimeter of tubule length 193. B: 3H radioactivity of collected tubular fluid is precipitable by trichloroacetic acid (TCA), indicating that albumin is not hydrolyzed in tubular lumen. 3H radioactivity appearing in tubular fluid is TCA soluble, indicating that absorbed albumin is hydrolyzed within tubular cells and negligible amounts of protein are transported intact across epithelium.

From Park and Maack 193
Figure 10. Figure 10.

Kinetics of albumin absorption in isolated perfused proximal convoluted tubules of rabbit. Absorption curve has two components: high‐capacity–low‐affinity uptake component ( = 3.7 ng/min/mm tubule length; apparent Km = 1.2 mg/ml) that saturates only at very high tubular fluid concentrations of albumin and low‐capacity component (insert) with apparent Km near physiological tubular fluid concentrations of albumin ( = 0.064 ng/min/mm tubule length; apparent Km = 0.031 mg/ml).

From Park and Maack 193
Figure 11. Figure 11.

Hydrolysis and accumulation of cytochrome c (CYT‐c) in isolated perfused rat kidney. Left: Efflux of 14C radioactivity from kidneys preloaded with [14CH3]cytochrome c and either low or high concentrations of unlabeled cytochrome c. Results are represented as percentage of [14CH3] cytochrome c initially accumulated in kidney tissue (ordinate) against time of perfusion in min (abscissa). 14C radioactivity accumulated in kidney tissue is intact [14CH3]cytochrome c; that released to perfusate is [14CH3]lysine, the labeled amino acid in [14CH3]cytochrome c (see Fig. 12). Fractional efflux of radioactivity (fractional hydrolysis of cytochrome c) decreases markedly at high concentrations of absorbed cytochrome c. Right: Accumulation (circles) and hydrolysis (triangles) of cytochrome c (ordinate) plotted against time of perfusion in min (abscissa). Renal hydrolysis of cytochrome c saturates at lower concentrations than its renal accumulation, because hydrolysis saturates before absorption of this protein (see text and ref. 22).

From Camargo et al. 23
Figure 12. Figure 12.

Effect of lysosomotropic weak bases (NH4Cl or chloroquine) on renal hydrolysis of absorbed cytochrome c in isolated perfused rat kidneys. A: Efflux of radioactivity in kidneys preloaded with [14CH3]cytochrome c and perfused under control conditions or in presence of NH4Cl or chloroquine. Lysosomotropic weak bases practically abolish efflux of radioactivity (hydrolysis of cytochrome c) from isolated kidney. B: Reversibility of NH4Cl effect. Removal of NH4Cl from perfusate immediately reverses its inhibitory effect on hydrolysis of absorbed cytochrome c (for methodological details of this reversibility experiment, see ref. 22). C: Sephadex G‐50 chromatograms of radioactivity present in kidney tissue (top) and perfusate (bottom) by end of efflux experiments shown in A. Intact [14CH3]cytochrome c detectable in much larger concentrations in kidneys treated with NH4Cl than in control kidneys. [14CH3]lysine detected in large concentrations in perfusate of control kidneys, indicating extensive hydrolysis of absorbed cytochrome c to amino acids that are then returned to perfusate. NH4Cl markedly reduces appearance of [14CH3]lysine in perfusate. As a whole, data indicate major importance of acid pH of lysosomes in disposal of absorbed proteins.

From Camargo et al. 22
Figure 13. Figure 13.

Tubular absorption (J3H3C‐ALB; closed circles) and hydrolysis (3H3; open circles) of [3H3C]albumin (ALB) in isolated proximal convoluted tubules of rabbit perfused with 36.4 μg/ml of labeled albumin. Approximately 50 min from beginning of perfusion elapsed before steady state was reached in which absorption and hydrolysis of albumin become equal. At this point, final steady‐state concentration of absorbed albumin in proximal tubular cells is approximately 5 ng/mm tubule length.

From Park 191
Figure 14. Figure 14.

Plasma immunoreactive glucagon (IRG) in control, sham‐operated rats (C); ureteral‐ligated rats (BUL); nephrectomized rats (Nx); and urine‐autoinfused rats (UA). Bars represent relative concentrations of different molecular weight forms of immunoreactive glucagon as determined by chromatographic procedures: C‐Peak, 3,500 Da; B‐peak, 9,000 Da; A‐peak, 40,000 Da. Total IRG is markedly increased in nephrectomized and ureteral‐ligated rats compared with control and urine‐autoinfused rats. In control and urine‐autoinfused rats, ∼90% of total IRG is in 3,500 Da form (C‐peak). Hyperglucagonemia in ureteral‐ligated rats is mostly due to increase in 3,500 Da form; that in nephrectomized rats due to major increase in both 3,500 and 9,000 Da forms.

From Emmanouel et al. 63
Figure 15. Figure 15.

Renal extraction and specific binding of atrial natriuretic factor (ANF) in isolated perfuse rat kidney. A: Perfusate decay of [125I]ANF1–28 in filtering and nonfiltering kidneys. Perfusate decay of [125I]ANF1–28 was very fast and only slightly faster in filtering compared with nonfiltering kidneys. TCAppt, trichloroacetic acid precipitable. *P < 0.05 vs. nonfiltering kidney. B: Perfusate decay of [125I]ANF1–28 at increasing perfusate concentrations of unlabeled ANF1–28 in nonfiltering kidneys. Fractional decay rate decreased with increasing concentrations of ANF1–28, demonstrating that renal extraction of ANF is a saturable phenomenon. C: High‐pressure liquid chromatogram of radioactivity eluted from kidney tissue by acid wash at end of perfusion of nonfiltering kidney with [125I]ANF1–28, indicating that intact peptide rather than labeled hydrolytic products are specifically bound to membrane receptors. Dashed lines, gradient of acetonitrile (CH3CN). D: Specific competition binding curves of ANF1–28 to whole‐kidney tissue (WK), outer cortex (OC), and papilla (P) in nonfiltering isolated kidneys. From depicted curves, density and apparent affinity of ANF receptors were calculated and are given in text. B/F, tissue/perfusate concentration of ANF1–28; F, molar (M) perfusate concentration of ANF1–28.

From Suzuki et al. 258
Figure 16. Figure 16.

Competition for renal binding and effects between native atrial natriuretic factor (ANF1–28) and C‐ANF4–23, a specific ligand of ANF clearance (C) receptors, in isolated perfused rat kidney. Top: Competition for binding between [125I]ANF1–28 and ANF1–28 or C‐ANF4–23 in whole kidney (A), outer cortex (B), and papilla (C). C‐ANF4–23 competes for >98% of ANF1–28‐binding sites in whole kidney and kidney cortex and with ∼60% of ANF1–28‐binding sites in papilla. This indicates that most renal receptors of ANF are C‐ANF receptors. Bottom: Effects of ANF1–28 (closed triangles), C‐ANF4–23 (open circles), and ANF1–28 + C‐ANF4–23 (open squares) on glomerular filtration rate (A) and sodium excretion (B) in isolated perfused rat kidney. In experiments in which C‐ANF4–23 was used (open circles, lower panel, and open squares, upper panel), analog was added to perfusate to final concentration of 0.1 μM at C0. Closed circles, lower panel, time control experiments. Increasing amounts of ANF1–28 were added to perfusate at final concentrations shown on abscissa. C‐ANF4–23, at concentration that leads to >98% of occupancy of total ANF receptor population in whole kidney and kidney cortex, has no effect of its own on GFR and sodium excretion and does not antagonize ANF1–28 effects on these parameters (open squares) or any other effect of native ANF1–28 145. As a whole, data indicate that overwhelming majority of specific binding sites of ANF in kidney are biologically silent, because C‐ANF receptors do not mediate any known renal functional effects of the hormone. A major function of C‐ANF receptors in kidney and vascular tissues is to remove endogenous ANF from circulation (see also Fig. 17).

From Maack et al. 145, copyright 1987 by the AAAS
Figure 17. Figure 17.

Clearance function of C‐ANF receptors. Plasma disappearance of trichloroacetic acid (TCA)–precipitable (ppt) radioactivity after administration of [125I]ANF1–28 in rat in control conditions (closed circles) and in presence of 1 μg·min−1/kg body wt of C‐ANF4–23 (closed triangles) or 10 μg·min−1/kg body wt of C‐ANF4–23 (open circles). High‐performance liquid chromatography of plasma samples during decay shows TCA‐precipitable radioactivity is measure of intact [125I]ANF1–28 (see ref. 1). At each time point during first 6 min of plasma decay curve, plasma concentration of administered [125I]ANF1–28 is significantly higher (*P<0.05) in presence than in absence of blockade of C‐ANF receptors by C‐ANF4–23. Pharmacokinetic parameters derived from curves show that C‐ANF4–23 markedly decreases apparent volume of distribution and metabolic clearance rate of [125I]ANF1–28 in dose‐related manner. For details, see text and Almeida et al. 1.

From Almeida et al. 1


Figure 1.

Schematic representation of endocytosis and intracellular transport of proteins. CP, coated pit; CV, coated vesicle; MVE, multivesicular endosome; MVB, multivesicular body; R, receptor. See text for description.

From Wall and Maack 270


Figure 2.

Renal accumulation of low‐molecular‐weight proteins (LMWP) in isolated perfused rat kidney in control conditions, or in presence of metabolic inhibitors, or in absence of filtration. rLZM, rat lysozyme; INS, insulin; rGH, rat growth hormone; bPTH, bovine parathyroid hormone; IAA, iodoacetate (10 mM); KCN, potassium cyanide (3 mM). LMWP are markedly accumulated in renal tissue, a phenomenon practically abolished by metabolic inhibitors or when kidneys are perfused in nonfiltering mode.

From Maack et al. 138


Figure 3.

Schematic representation of factors affecting filtration of macromolecules. Glomerular–capillary interface is represented with hypothetical pores of fixed dimensions, where Δx is pore length and A is pore diameter. Cp, protein concentration in glomerular capillary plasma; CF, protein concentration in glomerular filtrate; GFR, glomerular filtration rate; a, molecular dimension hindrance; b, steric hindrance; C, viscous drag; d, electrical hindrance, e, protein‐protein binding. Proteins with dimensions larger than the size of “pores” or bound to larger plasma proteins are not filtered (a, e). Proteins in which at least one diameter is smaller than diameter of “pores” are restricted in passage to glomerular filtrate by steric hindrance, viscous drag, and electrical hindrance (b, c, d). Electrical hindrance retards passage of negatively charged proteins and favors passage of positively charged proteins to glomerular filtrate. Steric hindrance, viscous drag, and electrical hindrance are more pronounced for intermediate‐sized proteins and have relatively little influence on filtration of low‐molecular‐weight proteins (for detailed quantitative description of glomerular permselectivity to macromolecules and proteins, see refs. 16,21,45,121,122,189,190,222).

From Maack and Sherman 143


Figure 4.

Tubular absorption of proteins after injection into surface proximal and distal tubules of rat. Results given as percentages of radioactivity recovered in ureteral urine after injection of [131I]iothalamate (nonreabsorbable substance), [131I]human serum albumin (RISA), and [131I]pork insulin. Proteins are extensively absorbed when injected into early proximal but not late proximal or early distal tubules. Absorption of insulin is proportionately greater than that of albumin and is not saturated over range of concentrations shown.

From Cortney et al. 40


Figure 5.

Renal titration curves of lysozyme (LZM, top) and cytochrome c (CYT C, bottom) in isolated perfused rat kidney. U, urinary concentration of CYT c; V, urine flow rate; P, plasma concentration of CYT c. Tm, tubular maximum of absorption; KPL, filtered loads of protein that lead to half‐maximal absorption (dashed lines); GFR, glomerular filtration rate; GSC, glomerular sieving coefficient of CYT c. See text for description.

From Sumpio and Maack 257


Figure 6.

Effect of iodoacetate (IAA) on albumin absorption (JALB) and fluid reabsorption (Jv) in isolated perfused proximal convoluted tubules of rabbit. Results expressed as percentages of control values obtained before addition of IAA (4 mM) to bathing solution. IAA practically abolished JALB, and inhibited JV to a smaller extent than JALB.

From Park and Maack 193


Figure 7.

Competition for tubular uptake between lysozyme and cytochrome c in isolated perfused rat kidney. Filtered load of cytochrome c was constant at approximately 1 μg/min; lysozyme loads increased stepwise to values indicated on abscissa.

From Sumpio and Maack 257


Figure 8.

Schematic representation of selective constraint model for tubular absorption of proteins. See text for description.

From Sumpio and Maack 257


Figure 9.

Absorption and fate of albumin in isolated perfused proximal convoluted tubules of rabbit. Tubules were perfused for approximately 1 h with perfusion fluid containing 0.03 mg/ml of [3H3C]albumin. A: 3H radioactivity absorbed from tubular lumen appears in bathing solution; only small proportion remains in tubular cells at end of perfusion. Rate of efflux of radioactivity from lumen corresponds to rate of albumin absorption of approximately 10% of perfused load of albumin per millimeter of tubule length 193. B: 3H radioactivity of collected tubular fluid is precipitable by trichloroacetic acid (TCA), indicating that albumin is not hydrolyzed in tubular lumen. 3H radioactivity appearing in tubular fluid is TCA soluble, indicating that absorbed albumin is hydrolyzed within tubular cells and negligible amounts of protein are transported intact across epithelium.

From Park and Maack 193


Figure 10.

Kinetics of albumin absorption in isolated perfused proximal convoluted tubules of rabbit. Absorption curve has two components: high‐capacity–low‐affinity uptake component ( = 3.7 ng/min/mm tubule length; apparent Km = 1.2 mg/ml) that saturates only at very high tubular fluid concentrations of albumin and low‐capacity component (insert) with apparent Km near physiological tubular fluid concentrations of albumin ( = 0.064 ng/min/mm tubule length; apparent Km = 0.031 mg/ml).

From Park and Maack 193


Figure 11.

Hydrolysis and accumulation of cytochrome c (CYT‐c) in isolated perfused rat kidney. Left: Efflux of 14C radioactivity from kidneys preloaded with [14CH3]cytochrome c and either low or high concentrations of unlabeled cytochrome c. Results are represented as percentage of [14CH3] cytochrome c initially accumulated in kidney tissue (ordinate) against time of perfusion in min (abscissa). 14C radioactivity accumulated in kidney tissue is intact [14CH3]cytochrome c; that released to perfusate is [14CH3]lysine, the labeled amino acid in [14CH3]cytochrome c (see Fig. 12). Fractional efflux of radioactivity (fractional hydrolysis of cytochrome c) decreases markedly at high concentrations of absorbed cytochrome c. Right: Accumulation (circles) and hydrolysis (triangles) of cytochrome c (ordinate) plotted against time of perfusion in min (abscissa). Renal hydrolysis of cytochrome c saturates at lower concentrations than its renal accumulation, because hydrolysis saturates before absorption of this protein (see text and ref. 22).

From Camargo et al. 23


Figure 12.

Effect of lysosomotropic weak bases (NH4Cl or chloroquine) on renal hydrolysis of absorbed cytochrome c in isolated perfused rat kidneys. A: Efflux of radioactivity in kidneys preloaded with [14CH3]cytochrome c and perfused under control conditions or in presence of NH4Cl or chloroquine. Lysosomotropic weak bases practically abolish efflux of radioactivity (hydrolysis of cytochrome c) from isolated kidney. B: Reversibility of NH4Cl effect. Removal of NH4Cl from perfusate immediately reverses its inhibitory effect on hydrolysis of absorbed cytochrome c (for methodological details of this reversibility experiment, see ref. 22). C: Sephadex G‐50 chromatograms of radioactivity present in kidney tissue (top) and perfusate (bottom) by end of efflux experiments shown in A. Intact [14CH3]cytochrome c detectable in much larger concentrations in kidneys treated with NH4Cl than in control kidneys. [14CH3]lysine detected in large concentrations in perfusate of control kidneys, indicating extensive hydrolysis of absorbed cytochrome c to amino acids that are then returned to perfusate. NH4Cl markedly reduces appearance of [14CH3]lysine in perfusate. As a whole, data indicate major importance of acid pH of lysosomes in disposal of absorbed proteins.

From Camargo et al. 22


Figure 13.

Tubular absorption (J3H3C‐ALB; closed circles) and hydrolysis (3H3; open circles) of [3H3C]albumin (ALB) in isolated proximal convoluted tubules of rabbit perfused with 36.4 μg/ml of labeled albumin. Approximately 50 min from beginning of perfusion elapsed before steady state was reached in which absorption and hydrolysis of albumin become equal. At this point, final steady‐state concentration of absorbed albumin in proximal tubular cells is approximately 5 ng/mm tubule length.

From Park 191


Figure 14.

Plasma immunoreactive glucagon (IRG) in control, sham‐operated rats (C); ureteral‐ligated rats (BUL); nephrectomized rats (Nx); and urine‐autoinfused rats (UA). Bars represent relative concentrations of different molecular weight forms of immunoreactive glucagon as determined by chromatographic procedures: C‐Peak, 3,500 Da; B‐peak, 9,000 Da; A‐peak, 40,000 Da. Total IRG is markedly increased in nephrectomized and ureteral‐ligated rats compared with control and urine‐autoinfused rats. In control and urine‐autoinfused rats, ∼90% of total IRG is in 3,500 Da form (C‐peak). Hyperglucagonemia in ureteral‐ligated rats is mostly due to increase in 3,500 Da form; that in nephrectomized rats due to major increase in both 3,500 and 9,000 Da forms.

From Emmanouel et al. 63


Figure 15.

Renal extraction and specific binding of atrial natriuretic factor (ANF) in isolated perfuse rat kidney. A: Perfusate decay of [125I]ANF1–28 in filtering and nonfiltering kidneys. Perfusate decay of [125I]ANF1–28 was very fast and only slightly faster in filtering compared with nonfiltering kidneys. TCAppt, trichloroacetic acid precipitable. *P < 0.05 vs. nonfiltering kidney. B: Perfusate decay of [125I]ANF1–28 at increasing perfusate concentrations of unlabeled ANF1–28 in nonfiltering kidneys. Fractional decay rate decreased with increasing concentrations of ANF1–28, demonstrating that renal extraction of ANF is a saturable phenomenon. C: High‐pressure liquid chromatogram of radioactivity eluted from kidney tissue by acid wash at end of perfusion of nonfiltering kidney with [125I]ANF1–28, indicating that intact peptide rather than labeled hydrolytic products are specifically bound to membrane receptors. Dashed lines, gradient of acetonitrile (CH3CN). D: Specific competition binding curves of ANF1–28 to whole‐kidney tissue (WK), outer cortex (OC), and papilla (P) in nonfiltering isolated kidneys. From depicted curves, density and apparent affinity of ANF receptors were calculated and are given in text. B/F, tissue/perfusate concentration of ANF1–28; F, molar (M) perfusate concentration of ANF1–28.

From Suzuki et al. 258


Figure 16.

Competition for renal binding and effects between native atrial natriuretic factor (ANF1–28) and C‐ANF4–23, a specific ligand of ANF clearance (C) receptors, in isolated perfused rat kidney. Top: Competition for binding between [125I]ANF1–28 and ANF1–28 or C‐ANF4–23 in whole kidney (A), outer cortex (B), and papilla (C). C‐ANF4–23 competes for >98% of ANF1–28‐binding sites in whole kidney and kidney cortex and with ∼60% of ANF1–28‐binding sites in papilla. This indicates that most renal receptors of ANF are C‐ANF receptors. Bottom: Effects of ANF1–28 (closed triangles), C‐ANF4–23 (open circles), and ANF1–28 + C‐ANF4–23 (open squares) on glomerular filtration rate (A) and sodium excretion (B) in isolated perfused rat kidney. In experiments in which C‐ANF4–23 was used (open circles, lower panel, and open squares, upper panel), analog was added to perfusate to final concentration of 0.1 μM at C0. Closed circles, lower panel, time control experiments. Increasing amounts of ANF1–28 were added to perfusate at final concentrations shown on abscissa. C‐ANF4–23, at concentration that leads to >98% of occupancy of total ANF receptor population in whole kidney and kidney cortex, has no effect of its own on GFR and sodium excretion and does not antagonize ANF1–28 effects on these parameters (open squares) or any other effect of native ANF1–28 145. As a whole, data indicate that overwhelming majority of specific binding sites of ANF in kidney are biologically silent, because C‐ANF receptors do not mediate any known renal functional effects of the hormone. A major function of C‐ANF receptors in kidney and vascular tissues is to remove endogenous ANF from circulation (see also Fig. 17).

From Maack et al. 145, copyright 1987 by the AAAS


Figure 17.

Clearance function of C‐ANF receptors. Plasma disappearance of trichloroacetic acid (TCA)–precipitable (ppt) radioactivity after administration of [125I]ANF1–28 in rat in control conditions (closed circles) and in presence of 1 μg·min−1/kg body wt of C‐ANF4–23 (closed triangles) or 10 μg·min−1/kg body wt of C‐ANF4–23 (open circles). High‐performance liquid chromatography of plasma samples during decay shows TCA‐precipitable radioactivity is measure of intact [125I]ANF1–28 (see ref. 1). At each time point during first 6 min of plasma decay curve, plasma concentration of administered [125I]ANF1–28 is significantly higher (*P<0.05) in presence than in absence of blockade of C‐ANF receptors by C‐ANF4–23. Pharmacokinetic parameters derived from curves show that C‐ANF4–23 markedly decreases apparent volume of distribution and metabolic clearance rate of [125I]ANF1–28 in dose‐related manner. For details, see text and Almeida et al. 1.

From Almeida et al. 1
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Article Title: Renal Handling of Proteins and Polypeptides
 

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Thomas Maack. Renal Handling of Proteins and Polypeptides. Compr Physiol 2011, Supplement 25: Handbook of Physiology, Renal Physiology: 2039-2082. First published in print 1992. doi: 10.1002/cphy.cp080244