Review ArticleCollecting duct renin: a major player in angiotensin II–dependent hypertension
Introduction
The renin-angiotensin system (RAS) plays a pivotal role in regulating renal sodium and water excretion and, therefore, in maintaining body sodium and fluid balance. It has generally been held that renin produced by the kidney cleaves liver-derived angiotensinogen (AGT) to form angiotensin (Ang) I in circulating blood, which is then converted into Ang II by angiotensin-converting enzyme (ACE) located at the luminal side of the endothelium in many tissues. More recently, an ACE homolog, ACE2, has been shown to cleave a single amino acid from Ang I to form Ang 1-9 and from Ang II to form Ang 1-7.1, 2, 3
The kidney possesses all the necessary RAS components to generate Ang II, as evidenced by the fact that its tissues contain much greater Ang II levels than the plasma.4, 5 Indeed, intrarenal Ang II contributes to the regulation of transport function and renal hemodynamics.6, 7, 8, 9, 10 The major fraction of Ang II present in the renal tissues is generated from AGT delivered to the kidney and from AGT locally produced by proximal tubule cells.11, 12 Although Ang I delivered to the kidney can also be converted into Ang II within the kidney,13, 14 the secretion of renin from juxtaglomerular (JG) cells and its delivery to the interstitium and microcirculation can form de novo Ang I in the renal interstitium.15 Furthermore, the presence of AGT in proximal tubule cells16 also provides a source for local generation of Ang I in the early part of the nephron. 17, 18 In addition, the localization of renin protein and messenger ribonucleic acid (mRNA) expression in principal cells of collecting ducts,19, 20, 21 along with the evidence of AGT in urine11 and ACE in the distal nephron segments,22, 23 indicate that the late part of the nephron is a likely site for intrarenal Ang II formation. Although, the intratubular concentrations of Ang II in the distal nephron remains undetermined, several studies support an important role of Ang II in the regulation of distal nephron sodium reabsorption via activation of AT1 receptors (AT1R) located on the apical aspects of the distal tubules and collecting ducts.13, 24, 25 The demonstration of a direct action of Ang II on the luminal amiloride-sensitive epithelial sodium channel13, 25 favors the scenario for a maintained stimulation of sodium reabsorption in the collecting duct and may help to explain the attenuation of the pressure-natriuretic in response to elevations in arterial blood pressure (BP) and the development and maintenance of hypertension during Ang II–dependent hypertension.26, 27, 28 In this review, we summarize our current understanding of independent regulation of the intrarenal RAS and discuss the hypothesis that inappropriate activation of renin in distal nephron segments and AGT synthesized and secreted by proximal tubules cells coordinate their actions to increase the formation of angiotensin peptides in the distal nephron segments, thereby playing a role in the development and progression of hypertension.
Section snippets
Augmentation of Intrarenal AGT and Ang II in Hypertension
The proximal tubule is a very active segment that participates in the reabsorption, degradation, and secretion of small peptides and bigger molecules such as AGT. Zou et al 29 demonstrated accumulation of Ang II in the whole kidney that is prevented by treatment with AT1R blockers. 29 The internalization of Ang II in the proximal tubules can occur via AT1R into endosomes and intermicrovillar cleft vesicles30 or by megalin,31 which targets Ang II to degradation protecting the cell against Ang II
Enhancement of Collecting Duct Renin in Ang II–dependent Hypertension
Renin in distal nephron segments may provide a pathway for Ang I generation from proximally delivered AGT. Although it is well established that plasma renin is primarily derived from the cells of the JG apparatus, renin transcript and protein have also been detected in renal tubular segments.20, 21, 41, 42, 43 Renin is expressed in principal cells of connecting tubules and cortical and medullary collecting ducts of kidneys of normal rats Ang II–dependent hypertensive rats, and two-kidney
Regulation of Renin in the Collecting Duct during Ang II–dependent Hypertension
The mechanisms responsible for the upregulation of renin in the CD during Ang II–dependent hypertension remain unclear. We have examined the gene expression of renin in the CD cells of different models of Ang II–dependent hypertension.20, 46, 53 In chronic Ang II–infused rats, renin expressed by principal cells of cortical connecting tubules and cortical and medullary CD is augmented.20 The increases in CD renin transcript as well as enzymatic activity in the medullary tissues of these rats
Potential Role of Enhanced Collecting Duct Renin in Ang II–dependent Hypertension
There is evidence for a compartmentalized and regional distribution of Ang II within the kidney. 63, 69 Renal interstitial fluid concentrations of Ang I and Ang II are much higher than in plasma. 63, 70 Early studies showed that medullary Ang II levels are higher than the cortical levels in normal rats.71 This concentrations increase even further in Ang II–infused hypertensive rats (Figure 2). It has been suggested that increases in Ang II content in association with high density of AT1Rs may
Conclusion
Emerging data indicate that collecting duct renin can be regulated independently from BP (Figure 3). These data help to explain how, even during states of JG renin suppression, the NCK can still maintain de novo intrarenal Ang II formation. From a functional perspective, enhanced AGT in urine of Ang II–dependent hypertensive rats reflects spillover of AGT from proximal nephron segments and substrate availability throughout the nephron. Thus, augmented renin in the collecting ducts along with
Acknowledgments
We thank to Dr. Tadashi Inagami, PhD (Vanderbilt University), for providing renin antibody used for these investigations. The authors acknowledge excellence technical assistance from Victoria L. Martin and Dale M. Seth. Digital images of histological specimens were obtained at the Imaging Core Facility of the Hypertension and Renal Center, Department of Physiology at Tulane University.
References (78)
- et al.
Intrarenal angiotensin II: interstitial and cellular levels and site of production
Kidney Int
(2001) - et al.
Urinary excretion of angiotensinogen reflects intrarenal angiotensinogen production
Kidney Int
(2002) - et al.
Expression of angiotensin I-converting enzymes and bradykinin B2 receptors in mouse inner medullary-collecting duct cells
Int Immunopharmacol
(2008) - et al.
Effects of unclipping and converting enzyme inhibition on bilateral renal function in two-kidney, one-clip Goldblatt hypertensive rats
Kidney Int
(1983) - et al.
The kidney androgen-regulated protein promoter confers renal proximal tubule cell-specific and highly androgen-responsive expression on the human angiotensinogen gene in transgenic mice
J Biol Chem
(1997) - et al.
Renin and kallikrein in connecting tubule of mouse
Kidney Int
(2003) - et al.
Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats
Kidney Int
(2007) Increased cyclooxygenase-2, hyperfiltration, glomerulosclerosis, and diabetic nephropathy: put the blame on the (pro)renin receptor?
Kidney Int
(2006)- et al.
Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway
Am J Pathol
(2008) - et al.
The renin-angiotensin system and cardiovascular Homeostasis
Angiotensin-converting enzyme 2 is an essential regulator of heart function
Nature
Contribution of Angiotensin-(1-7) to cardiovascular physiology and pathology
Curr Hypertens Rep
Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion
Am J Physiol Renal Physiol
Renal accumulation of circulating angiotensin II in angiotensin II-infused rats
Hypertension
Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors
Am J Physiol Renal Physiol
Contribution of angiotensin II internalization to intrarenal angiotensin II levels in rats
Am J Physiol Renal Physiol
Concentrations and actions of intraluminal angiotensin II
J Am Soc Nephrol
The intracrine hypothesis and intracellular peptide hormone action
Bioessays
Urinary angiotensinogen as an indicator of intrarenal Angiotensin status in hypertension
Hypertension
Angiotensin I conversion to angiotensin II stimulates cortical collecting duct sodium transport
Hypertension
Effects on renal hemodynamics of intra-arterial infusions of angiotensins I and II
Am J Physiol
Morphology, physiology, and molecular biology of renin secretion
Physiol Rev
Expression of angiotensinogen mRNA and protein in angiotensin II-dependent hypertension
J Am Soc Nephrol
Proximal tubular fluid, kidney, and plasma levels of angiotensin II in hypertensive ren-2 transgenic rats
Am J Physiol Renal Physiol
Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats
J Am Soc Nephrol
The collecting duct is the major source of prorenin in diabetes
Hypertension
Enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats
Hypertension
Elements of a paracrine tubular renin-angiotensin system along the entire nephron
Hypertension
Angiotensin I-converting enzyme activity in tubular fluid along the rat nephron
Am J Physiol Renal Physiol
Effect of luminal angiotensin II and ANP on early and late cortical distal tubule HCO3- reabsorption
Am J Physiol Renal Physiol
Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT(1) receptors
J Am Soc Nephrol
Angiotensin and angiotensin-converting enzyme tissue levels in two-kidney, one-clip hypertensive rats
Hypertension
Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension
Renal accumulation of circulating angiotensin II in angiotensin II-infused rats
Hypertension
Ang II accumulation in rat renal endosomes during Ang II-induced hypertension: role of AT(1) receptor
Hypertension
Megalin binds and internalizes angiotensin II
Am J Physiol Renal Physiol
Intrarenal angiotensin II and angiotensinogen augmentation in chronic angiotensin II-infused mice
Am J Physiol Renal Physiol
Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANG II feedback
Am J Physiol Renal Physiol
Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II
Am J Physiol Endocrinol Metab
Cited by (0)
This study was supported by the National Institute of Health through the National, Lung, and Blood Institute (HL-26371), the Eunice Kennedy Shriver National Institute of Child Health & Human Development (K12HD043451), the Institutional Developmental Award Program of the National Center for Research Resources (P20RR-017659), and the American Heart Association (0325269B).
Conflict of interest: none.