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Nonclassical Renin‐Angiotensin System and Renal Function

Mark C. Chappell

10.1002/cphy.c120002

Source: Volume 2, Issue 4, October 2012

Published online: October 2012

Full Article on Wiley Online Library



Abstract

The renin‐angiotensin system (RAS) constitutes one of the most important hormonal systems in the physiological regulation of blood pressure through renal and nonrenal mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, including kidney injury, and blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or blockade of the angiotensin type 1 receptor (AT1R) by selective antagonists constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS within the kidney and other tissues that the system is actually composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE‐Ang II‐AT1R axis that promotes vasoconstriction, water intake, sodium retention, and other mechanisms to maintain blood pressure, as well as increase oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the nonclassical RAS composed primarily of the AngII/Ang III‐AT2R pathway and the ACE2‐Ang‐(1‐7)‐AT7R axis generally opposes the actions of a stimulated Ang II‐AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and reduced oxidative stress. Moreover, increasing evidence suggests that these non‐classical RAS components contribute to the therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury, as well as contribute to normal renal function. © 2012 American Physiological Society. Compr Physiol 2:2733‐2752, 2012.

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Figure 1. Figure 1.

Scheme for the enzymatic cascade of angiotensin peptide formation and metabolism. Renin cleaves the precursor protein angiotensinogen (Aogen) at the Leu10‐Leu11 bond to angiotensin‐(1‐10) (Ang I), which is further processed to the biologically active peptides Ang‐(1‐8) (Ang II) by angiotensin converting enzyme (ACE) and Ang‐(1‐7) by endopeptidases such as neprilysin (NEP). Ang II undergoes further processing at the carboxy terminus by the carboxypeptidase ACE2 to yield Ang‐(1‐7) and at the amino terminus by aminopeptidase A (APA) to form Ang‐(2‐8) or Ang III. Ang‐(1‐7) is metabolized by ACE to form Ang‐(1‐5) and Ang III is further hydrolyzed by aminopeptidase N (APN) to yield Ang‐(3‐8) or Ang IV. Ang II can be directly cleaved by dipeptidyl aminopeptidase IV (DAP) to Ang IV. The novel peptide Ang‐(1‐12) is derived from the hydrolysis of the Tyr12‐Tyr12 bond of Aogen, although the identity of the enzyme that forms the peptides is not known to date. Adapted, with permission, from Chappell 33.
Figure 2. Figure 2.

Renal actions of the classical and nonclassical components of the renin‐angiotensin system. Ang II interacts with the AT1 receptor (AT1R) to increase renal vasoconstriction and sodium reabsorption, and promote inflammation and fibrosis. Ang IV may stimulate vasoconstriction through an interaction with the AT1R. Renin or prorenin binds to the prorenin receptor (PRR) to directly promote oxidative stress, fibrosis, and inflammation. Ang II or Ang III stimulates vasodilation, reduced vascular resistance, and natriuresis through activation of the AT2R and the generation of nitric oxide and arachidonate acid release. Ang‐(1‐7) recognizes the AT7R to stimulate vasodilation, diuresis and natriuresis, but reduce inflammation and fibrosis through increased generation of nitric oxide and prostaglandins. Ang IV may interact with the insulin regulated aminopeptidase (IRAP) to reduce vascular resistance through an increase in nitric oxide.
Figure 3. Figure 3.

Urinary excretion of angiotensinogen may arise from glomerular injury and filtration of circulating protein in the mRen2.Lewis rat. (A) Excretion of angiotensinogen or Aogen (uAGT; ug/kg/day) is increased in mRen2.Lewis rats fed a high‐salt diet (HS) compared to normal salt (NS). (B), (C) Aogen mRNA and protein expression in renal cortex are not increased by the HS diet in mRen2.Lewis rats. (D) Urinary and plasma forms of Aogen in HS mRen2.Lewis rats migrate at 60 and 55 kiloDaltons (kDa). Data are adapted, with permission, from Cohen et al. 43.
Figure 4. Figure 4.

Enzymatic metabolism of 125I‐Ang II in isolated sheep proximal tubules. 125I‐Ang II (AII) was incubated with 50 μg of proximal tubules membranes for 30 min at 37°C and the metabolites were separated by high performance liquid chromatography (HPLC). (A) Quantification of the peptidase activities for 125I‐AII metabolism from the sheep proximal tubule membranes expressed as the rate of metabolism products formed (fmol/mg/min). Conditions: Control (no inhibitors); +AP,CYS,CHM‐I (inhibitors for aminopeptidase, chymase, cysteine proteases); +NEP‐I (addition of neprilysin inhibitor); +ACE‐I (addition of ACE inhibitor); +ACE2‐I [addition of angiotensin converting enzyme 2 (ACE2) inhibitor]. Data are means; n = 4. (B) Influence of ACE2 inhibition on half‐life (t1/2) of 125I‐Ang II (AII) in proximal tubules. Conditions: control (no inhibitors); +MLN (only the ACE2 inhibitor). Data are means; n = 5; *P < 0.05 versus control. (C) Metabolism pathway for Ang II and Ang‐(1‐7) in sheep proximal tubules. Adapted, with permission, from Shaltout et al. 160.
Figure 5. Figure 5.

Deletion of tissue angiotensin converting enzyme (ACE) significantly reduces levels of Ang II but not Ang‐(1‐7) in mouse kidney. The HPLC/radioimmunoassay (RIA) analysis of pooled mouse kidney samples from wild‐type (upper panel) and tissue ACE knockout (tisACE −/−) mice (lower panel). The HPLC fractions were measured with Ang‐(1‐7) (fractions 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20), and Ang II (fractions 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39) RIAs, respectively. The arrows indicate the elution peak times for Ang‐(1‐7), Ang‐(4‐8), and Ang II. Inset: intrarenal concentration of Ang II and Ang‐(1‐7) expressed as fmol/mg protein in wild‐type and tisACE−/− mice, n = 8 per group; *P < 0.001 versus wild type. Adapted, with permission, from Modrall et al. 110.
Figure 6. Figure 6.

Expression of angiotensin‐(1‐12) in the kidney of the female mRen2.Lewis rat. (A) Immunofluorescent signal for rat Ang‐(1‐12) in the renal cortex of 15‐week‐old hemizygous mRen2.Lewis rat fed a normal‐salt (NS) diet reveals predominant staining of tubular elements, particularly in the apical aspects of the tubules (arrows). Binding of the primary antibody against the C‐terminus of rat Ang‐(1‐12) was followed by the secondary antibody conjugated to Alexa Fluor 562 (red fluorescence) and the nuclear marker stain DAPI (blue) (Lindsey and Chappell, unpublished results). (B) Comparison of excretion rates (pmol/kg/d) for Ang‐(1‐7), Ang II, and Ang‐(1‐12) in 15‐week‐old, hemizygous female mRen2.Lewis rat on NS diet 43. Ang II and Ang‐(1‐7) data are n = 6; Ang‐(1‐12) from same subset, n = 3. (C) HPLC/RIA analysis of Ang‐(1‐12) in extracted urine of female mRen2.Lewis rat. Arrows indicate retention times of Ang‐(1‐7) (A7); Ang II (A2), Ang I (A1), and Ang‐(1‐12) (A12) standards. The predominant immunoreactive peak corresponds to Ang‐(1‐12) (A12) (Chappell, unpublished results). HPLC conditions were 30% to 50% B over 25 min and 50% isocratic for 10 min at a flow rate of 0.35 mL/min [(A): 01.% HFBA and (B): 80% acetonitrile/0.1% HFBA] as described 110. Fractions were collected at 1 min intervals and analyzed by the Ang‐(1‐12) RIA.
Figure 7. Figure 7.

Autoradiography of Ang II binding sites in the fetal and adult sheep kidney. Frozen‐thawed kidney sections were incubated with receptor antagonists to the AT2 receptor (PD123319) or the AT1 receptor (losartan) in the presence of the nonselective antagonist 125I‐Sarthran (0.2 nmol/L). Nonspecific labeling was obtained by preincubation with the unlabeled Sarthran antagonist (5 μmol/L). Adapted from Gwathmey et al. 68.
Figure 8. Figure 8.

Sex differences in systolic blood pressure, proteinuria, and components of the renin‐angiotensin system in the renal cortex of mRen2.Lewis congenic rats. Systolic blood pressure is expressed in mmHg and proteinuria as mg per kilogram body weight per day (mg/kg/d). Intrarenal concentrations of Ang II and Ang‐(1‐7) are expressed as fmol peptide per mg protein (fmol/mg) and enzyme activities as fmol product per mg protein per min (fmol/mg/min) in 15‐week‐old hemizygous mRen2.Lewis rats, n = 5‐8 per group; **P < 0.01 or *P < 0.01. Adapted, with permission, from Pendergrass et al. 128.
Figure 9. Figure 9.

Immunocytochemical distribution of the Mas receptor in the adult sheep kidney and natriuretic influence of Ang‐(1‐7). Upper panel: signal for Mas receptor in proximal tubules (PT) and distal tubules but not glomerulus in renal cortex (A); positive staining of collecting ducts in cortex (B); Mas staining of thick ascending limb of Henle (TAL) and vasa recta (VR) in renal medulla; addition of the antigenic peptide for primary antibody abolishes Mas staining in adjacent tissue sections (D‐F). Binding of the primary antibody against the Mas receptor protein was followed by the secondary antibody conjugated to Alexa Fluor 488 (green fluorescence) and the nuclear marker stain DAPI (blue). Adapted, with permission, from Gwathmey et al. 70. Lower panel: Ang‐(1‐7) infusion increases sodium excretion (% of an acute sodium load) in control sheep as compared to saline infusion (vehicle). The natriuretic response to Ang‐(1‐7) was absent in sheep prenatally exposed to the glucocorticoid betamethasone (Beta). Data are means, n = 11‐12 sheep. Adapted, with permission, from Tang et al. 174.
Figure 10. Figure 10.

Ang‐(1‐7) increases nitric oxide and attenuates Ang II‐dependent increase in reactive oxygen species in isolated nuclei from renal cortex. (A) Ang‐(1‐7) exhibits greater potency than Ang II at the AT2R to stimulate nitric oxide (NO) as detected by diaminofluorescein [DAF; *P < 0.05 vs. Ang‐(1‐7)]. (B) The AT1R antagonist losartan (LOS) blocks the Ang II stimulation of ROS; the AT7R antagonist D‐Ala7‐Ang‐(1‐7) (DALA) and angiotensin converting enzyme 2 (ACE2) inhibitor MLN4760 (MLN) exacerbate the Ang II response (δP < 0.05 vs. Ang II); the AT2R antagonist PD123319 (PD) had no effect. (C) HPLC chromatograph of conversion of Ang II to Ang‐(1‐7) [Ang7] in isolated nuclei from sheep proximal tubules and inhibition by the ACE2 inhibitor MLN4763 (MLN). Adapted, with permission, from Gwathmey et al. 67,70.
Figure 11. Figure 11.

Scheme for the attenuation of the Ang II‐AT1 receptor signaling by Ang‐(1‐7). Ang II stimulates various signaling pathways including reactive oxygen species (ROS) that culminates in the activation of intracellular kinases (MAPK). Attenuation of Ang II signaling within the kidney occurs through amino and carboxy terminal metabolism to Ang III and Ang‐(1‐7) by aminopeptidase A (APN) and angiotensin converting enzyme 2 (ACE2), respectively. Formation of Ang‐(1‐7) will stimulate the generation of nitric oxide (NO) and cGMP that may antagonize the actions of Ang II, as well as complex superoxide (O2−) to form peroxynitrite (ONOO‐). In addition, Ang‐(1‐7) may activate intracellular phosphatases (PTP) to attenuate the Ang II‐induced phosphorylation of kinases. ACE may abrogate Ang‐(1‐7) signaling by enzymatic conversion to Ang‐(1‐5), which likely does not interact with the AT7/Mas receptor. Although not depicted, generation of Ang III from Ang II may contribute to increased formation of NO by stimulation of the AT2 receptor pathway. Adapted, with permission, from Chappell 33.


Figure 1.

Scheme for the enzymatic cascade of angiotensin peptide formation and metabolism. Renin cleaves the precursor protein angiotensinogen (Aogen) at the Leu10‐Leu11 bond to angiotensin‐(1‐10) (Ang I), which is further processed to the biologically active peptides Ang‐(1‐8) (Ang II) by angiotensin converting enzyme (ACE) and Ang‐(1‐7) by endopeptidases such as neprilysin (NEP). Ang II undergoes further processing at the carboxy terminus by the carboxypeptidase ACE2 to yield Ang‐(1‐7) and at the amino terminus by aminopeptidase A (APA) to form Ang‐(2‐8) or Ang III. Ang‐(1‐7) is metabolized by ACE to form Ang‐(1‐5) and Ang III is further hydrolyzed by aminopeptidase N (APN) to yield Ang‐(3‐8) or Ang IV. Ang II can be directly cleaved by dipeptidyl aminopeptidase IV (DAP) to Ang IV. The novel peptide Ang‐(1‐12) is derived from the hydrolysis of the Tyr12‐Tyr12 bond of Aogen, although the identity of the enzyme that forms the peptides is not known to date. Adapted, with permission, from Chappell 33.



Figure 2.

Renal actions of the classical and nonclassical components of the renin‐angiotensin system. Ang II interacts with the AT1 receptor (AT1R) to increase renal vasoconstriction and sodium reabsorption, and promote inflammation and fibrosis. Ang IV may stimulate vasoconstriction through an interaction with the AT1R. Renin or prorenin binds to the prorenin receptor (PRR) to directly promote oxidative stress, fibrosis, and inflammation. Ang II or Ang III stimulates vasodilation, reduced vascular resistance, and natriuresis through activation of the AT2R and the generation of nitric oxide and arachidonate acid release. Ang‐(1‐7) recognizes the AT7R to stimulate vasodilation, diuresis and natriuresis, but reduce inflammation and fibrosis through increased generation of nitric oxide and prostaglandins. Ang IV may interact with the insulin regulated aminopeptidase (IRAP) to reduce vascular resistance through an increase in nitric oxide.



Figure 3.

Urinary excretion of angiotensinogen may arise from glomerular injury and filtration of circulating protein in the mRen2.Lewis rat. (A) Excretion of angiotensinogen or Aogen (uAGT; ug/kg/day) is increased in mRen2.Lewis rats fed a high‐salt diet (HS) compared to normal salt (NS). (B), (C) Aogen mRNA and protein expression in renal cortex are not increased by the HS diet in mRen2.Lewis rats. (D) Urinary and plasma forms of Aogen in HS mRen2.Lewis rats migrate at 60 and 55 kiloDaltons (kDa). Data are adapted, with permission, from Cohen et al. 43.



Figure 4.

Enzymatic metabolism of 125I‐Ang II in isolated sheep proximal tubules. 125I‐Ang II (AII) was incubated with 50 μg of proximal tubules membranes for 30 min at 37°C and the metabolites were separated by high performance liquid chromatography (HPLC). (A) Quantification of the peptidase activities for 125I‐AII metabolism from the sheep proximal tubule membranes expressed as the rate of metabolism products formed (fmol/mg/min). Conditions: Control (no inhibitors); +AP,CYS,CHM‐I (inhibitors for aminopeptidase, chymase, cysteine proteases); +NEP‐I (addition of neprilysin inhibitor); +ACE‐I (addition of ACE inhibitor); +ACE2‐I [addition of angiotensin converting enzyme 2 (ACE2) inhibitor]. Data are means; n = 4. (B) Influence of ACE2 inhibition on half‐life (t1/2) of 125I‐Ang II (AII) in proximal tubules. Conditions: control (no inhibitors); +MLN (only the ACE2 inhibitor). Data are means; n = 5; *P < 0.05 versus control. (C) Metabolism pathway for Ang II and Ang‐(1‐7) in sheep proximal tubules. Adapted, with permission, from Shaltout et al. 160.



Figure 5.

Deletion of tissue angiotensin converting enzyme (ACE) significantly reduces levels of Ang II but not Ang‐(1‐7) in mouse kidney. The HPLC/radioimmunoassay (RIA) analysis of pooled mouse kidney samples from wild‐type (upper panel) and tissue ACE knockout (tisACE −/−) mice (lower panel). The HPLC fractions were measured with Ang‐(1‐7) (fractions 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20), and Ang II (fractions 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39) RIAs, respectively. The arrows indicate the elution peak times for Ang‐(1‐7), Ang‐(4‐8), and Ang II. Inset: intrarenal concentration of Ang II and Ang‐(1‐7) expressed as fmol/mg protein in wild‐type and tisACE−/− mice, n = 8 per group; *P < 0.001 versus wild type. Adapted, with permission, from Modrall et al. 110.



Figure 6.

Expression of angiotensin‐(1‐12) in the kidney of the female mRen2.Lewis rat. (A) Immunofluorescent signal for rat Ang‐(1‐12) in the renal cortex of 15‐week‐old hemizygous mRen2.Lewis rat fed a normal‐salt (NS) diet reveals predominant staining of tubular elements, particularly in the apical aspects of the tubules (arrows). Binding of the primary antibody against the C‐terminus of rat Ang‐(1‐12) was followed by the secondary antibody conjugated to Alexa Fluor 562 (red fluorescence) and the nuclear marker stain DAPI (blue) (Lindsey and Chappell, unpublished results). (B) Comparison of excretion rates (pmol/kg/d) for Ang‐(1‐7), Ang II, and Ang‐(1‐12) in 15‐week‐old, hemizygous female mRen2.Lewis rat on NS diet 43. Ang II and Ang‐(1‐7) data are n = 6; Ang‐(1‐12) from same subset, n = 3. (C) HPLC/RIA analysis of Ang‐(1‐12) in extracted urine of female mRen2.Lewis rat. Arrows indicate retention times of Ang‐(1‐7) (A7); Ang II (A2), Ang I (A1), and Ang‐(1‐12) (A12) standards. The predominant immunoreactive peak corresponds to Ang‐(1‐12) (A12) (Chappell, unpublished results). HPLC conditions were 30% to 50% B over 25 min and 50% isocratic for 10 min at a flow rate of 0.35 mL/min [(A): 01.% HFBA and (B): 80% acetonitrile/0.1% HFBA] as described 110. Fractions were collected at 1 min intervals and analyzed by the Ang‐(1‐12) RIA.



Figure 7.

Autoradiography of Ang II binding sites in the fetal and adult sheep kidney. Frozen‐thawed kidney sections were incubated with receptor antagonists to the AT2 receptor (PD123319) or the AT1 receptor (losartan) in the presence of the nonselective antagonist 125I‐Sarthran (0.2 nmol/L). Nonspecific labeling was obtained by preincubation with the unlabeled Sarthran antagonist (5 μmol/L). Adapted from Gwathmey et al. 68.



Figure 8.

Sex differences in systolic blood pressure, proteinuria, and components of the renin‐angiotensin system in the renal cortex of mRen2.Lewis congenic rats. Systolic blood pressure is expressed in mmHg and proteinuria as mg per kilogram body weight per day (mg/kg/d). Intrarenal concentrations of Ang II and Ang‐(1‐7) are expressed as fmol peptide per mg protein (fmol/mg) and enzyme activities as fmol product per mg protein per min (fmol/mg/min) in 15‐week‐old hemizygous mRen2.Lewis rats, n = 5‐8 per group; **P < 0.01 or *P < 0.01. Adapted, with permission, from Pendergrass et al. 128.



Figure 9.

Immunocytochemical distribution of the Mas receptor in the adult sheep kidney and natriuretic influence of Ang‐(1‐7). Upper panel: signal for Mas receptor in proximal tubules (PT) and distal tubules but not glomerulus in renal cortex (A); positive staining of collecting ducts in cortex (B); Mas staining of thick ascending limb of Henle (TAL) and vasa recta (VR) in renal medulla; addition of the antigenic peptide for primary antibody abolishes Mas staining in adjacent tissue sections (D‐F). Binding of the primary antibody against the Mas receptor protein was followed by the secondary antibody conjugated to Alexa Fluor 488 (green fluorescence) and the nuclear marker stain DAPI (blue). Adapted, with permission, from Gwathmey et al. 70. Lower panel: Ang‐(1‐7) infusion increases sodium excretion (% of an acute sodium load) in control sheep as compared to saline infusion (vehicle). The natriuretic response to Ang‐(1‐7) was absent in sheep prenatally exposed to the glucocorticoid betamethasone (Beta). Data are means, n = 11‐12 sheep. Adapted, with permission, from Tang et al. 174.



Figure 10.

Ang‐(1‐7) increases nitric oxide and attenuates Ang II‐dependent increase in reactive oxygen species in isolated nuclei from renal cortex. (A) Ang‐(1‐7) exhibits greater potency than Ang II at the AT2R to stimulate nitric oxide (NO) as detected by diaminofluorescein [DAF; *P < 0.05 vs. Ang‐(1‐7)]. (B) The AT1R antagonist losartan (LOS) blocks the Ang II stimulation of ROS; the AT7R antagonist D‐Ala7‐Ang‐(1‐7) (DALA) and angiotensin converting enzyme 2 (ACE2) inhibitor MLN4760 (MLN) exacerbate the Ang II response (δP < 0.05 vs. Ang II); the AT2R antagonist PD123319 (PD) had no effect. (C) HPLC chromatograph of conversion of Ang II to Ang‐(1‐7) [Ang7] in isolated nuclei from sheep proximal tubules and inhibition by the ACE2 inhibitor MLN4763 (MLN). Adapted, with permission, from Gwathmey et al. 67,70.



Figure 11.

Scheme for the attenuation of the Ang II‐AT1 receptor signaling by Ang‐(1‐7). Ang II stimulates various signaling pathways including reactive oxygen species (ROS) that culminates in the activation of intracellular kinases (MAPK). Attenuation of Ang II signaling within the kidney occurs through amino and carboxy terminal metabolism to Ang III and Ang‐(1‐7) by aminopeptidase A (APN) and angiotensin converting enzyme 2 (ACE2), respectively. Formation of Ang‐(1‐7) will stimulate the generation of nitric oxide (NO) and cGMP that may antagonize the actions of Ang II, as well as complex superoxide (O2−) to form peroxynitrite (ONOO‐). In addition, Ang‐(1‐7) may activate intracellular phosphatases (PTP) to attenuate the Ang II‐induced phosphorylation of kinases. ACE may abrogate Ang‐(1‐7) signaling by enzymatic conversion to Ang‐(1‐5), which likely does not interact with the AT7/Mas receptor. Although not depicted, generation of Ang III from Ang II may contribute to increased formation of NO by stimulation of the AT2 receptor pathway. Adapted, with permission, from Chappell 33.

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Article Title: Nonclassical Renin‐Angiotensin System and Renal Function
 

How to Cite

Mark C. Chappell. Nonclassical Renin‐Angiotensin System and Renal Function. Compr Physiol 2012, 2: 2733-2752. doi: 10.1002/cphy.c120002