Impaired Pressure Natriuresis Research Articles

Bilateral renal denervation prevents the development of hypertension during diet-induced obesity in male rats.

What is the central question of this study? What is the role of the renal nerves in the development of obesity, hyperlipidaemia and hypertension during the long-term feeding of a moderately high-fat diet in male obesity-prone rats? What is the main finding and its importance? The renal nerves play a prominent mediatory role, without influencing the establishment of visceral adiposity and atherogenic hyperlipidaemia, in the induction and progression of pressure natriuresis impairment and hypertension during the developmental period of diet-induced obesity. Feeding a moderately high-fat (MHF) diet in male Sprague-Dawley rats induces obesity, pressure natriuresis impairment and hypertension. This study investigated the role of the renal nerves in the impaired pressure natriuresis and hypertension caused by feeding a MHF diet. After collecting baseline data on day 0, 12 rats remained on a low-fat diet (LF group) while the others were switched onto a MHF diet and diverged into obesity-resistant (OR) or obesity-prone (OP). After 4weeks, half of the OR and OP rats underwent bilateral renal denervation (BRD) to generate four groups: OR, OR/BRD, OP and OP/BRD (n=12). During 10weeks, body weight, obesity index, systolic pressure and renal excretory function were measured regularly. After 10weeks, renal excretory responses to acute salt loading and renal autoregulation were evaluated. The OP and OP/BRD groups had greater increases of body weight and obesity index during the dietary period compared to the other groups, and by week 10 their body weight (425.1±7.2 and 411.9±5.1g) became considerably larger than that of the LF group (358.5±6.2g). Renal sodium excretion was reduced by ∼20% at week 4 in the OP and OP/BRD groups, while only the OP group had lower sodium excretion at weeks 6-8 and higher systolic pressure over weeks 5-10 than the other groups and its week 10 systolic pressure reached 138.1±6.7 versus 123.6±2.7mmHg of the LF group. The OP group showed delayed renal excretory responses to salt loading with rightward and downward shifts in renal autoregulatory curves. Therefore, the renal nerves exert a main mediatory role in the development of pressure natriuresis impairment and hypertension as obesity is established due to the long-term consumption of the MHF diet in male OP rats.

Hypertension due to loss of water

In the current issue of Acta Physiologica, two papers are published investigating the development of arterial hypertension under conditions of pathological loss of free water in two disease models. Kovaric et al 1 studied rats with chronic renal failure, shedding excessive free water via their remnant kidney due to a hypostenuric concentrating defect. Wild et al. 2 investigated a transgenic mouse model for psoriasis, losing free water via the psoriatic skin lesions. In both cases the animals displayed hypertension, cutaneous vasoconstriction, and metabolic adaptations towards enhanced production of urea and organic osmolytes typical for a phylogenetically ancient water conservation response termed aestivation 3 . The international consortia of investigators spearheaded by Titze, Karbach, and Kitada therefore conclude that in both cases the hypertension was due to cutaneous vasoconstriction in an attempt to limit epidermal water loss. Because in either case the hypertension was associated with loss of water, and thus with hypo- rather than hypervolemia, the authors argue, that this concept of pathogenesis of hypertension is antipodal to the classic view that relies on hypervolemia due to sodium retention.

Temporal patterns of alterations in obesity index, lipid profile, renal function and blood pressure during the development of hypertension in male, but not female, rats fed a moderately high-fat diet

Context: Male Sprague-Dawley rats consuming a moderately high-fat (MHF)-diet diverge into obesity-prone (OP) with hypertension and obesity-resistant.Objectives: To study the temporal inter-relationships between body-weight, obesity-index, plasma lipid-profile, renal functional parameters and systolic-pressure alterations during 10-weeks feeding MHF or normal diet to male and female rats.Methods: Body-weight, obesity-index and systolic-pressure were measured weekly, while metabolic-cage and blood-sampling protocols were performed every other week. After 10-weeks, renal excretory responses to acute salt-loading and renal autoregulation were examined.Results: The male-OP group had progressively increased body-weight, plasma-triglyceride and systolic-pressure from Weeks 2, 4 and 5, respectively, lower renal sodium-excretion at weeks 4–8 and finally, delayed excretory response to salt-loading and rightward and downward shifts in renal autoregulatory curves compared to all other groups.Conclusion: Feeding the MHF-diet in male-OP rats led to a greater weight-gain and adiposity followed by the development of atherogenic-hyperlipidaemia and persistently impaired pressure-natriuresis to induce hypertension.

Effects of empagliflozin on nondiabetic salt-sensitive hypertension in uninephrectomized rats

Impaired pressure natriuresis (PN) underlies salt-sensitive hypertension, and renal inflammation and hypoxia-inducible factor-1 (HIF-1) have been implicated in the modulation of systemic hypertension. Although sodium–glucose cotransporter-2 (SGLT2) inhibitors were reported to lower blood pressure (BP) in type 2 diabetes mellitus, whether they have a role in nondiabetic hypertensive kidney diseases is unclear. The present study was undertaken to investigate whether nondiabetic salt-sensitive hypertension and accompanying renal inflammation are ameliorated by SGLT2 inhibition. Male Sprague-Dawley rats were randomly divided into three groups: sham controls (SCs), uninephrectomized controls (UCs), and empagliflozin-treated rats (ETs). All rats were fed a rodent diet with 8% NaCl throughout the study period. Empagliflozin was orally administered for 3 weeks after uninephrectomy. Systolic blood pressure was recorded weekly, and kidneys were harvested for immunoblotting, immunohistochemistry, and quantitative PCR analysis at the end of the animal experiment. Systolic BP was significantly decreased in ETs that were orally given empagliflozin for 3 weeks after uninephrectomy. Although ETs did not show any increase in weekly measured urine sodium, the right-shifted PN relationship in UCs was improved by empagliflozin treatment. The expression of HIF-1α was increased in the renal outer medulla of ETs. Consistent with this, HIF prolyl-hydroxylase-2 protein and mRNA were decreased in ETs. The abundance of CD3 and ED-1 immunostaining in UCs was reduced by empagliflozin treatment. The increased IL-1ß, gp91phox, and NOX4 mRNA levels in UCs were also reversed. Empagliflozin restored impaired PN in nondiabetic hypertensive kidney disease in association with increased renal medullary expression of HIF-1α and amelioration of renal inflammation.

Alteration of Tight Junction Protein Expression in Dahl Salt-Sensitive Rat Kidney

Background/Aims: Altered pressure natriuresis is an important mechanism of hypertension, but it remains elusive at the molecular level. We hypothesized that in the kidney, tight junctions (TJs) may have a role in pressure natriuresis because paracellular NaCl transport affects interstitial hydrostatic pressure. Methods: To assess the association of salt-sensitive hypertension with altered renal TJ protein expression, Dahl salt-sensitive (SS) and salt-resistant (SR) rats were put on an 8% NaCl-containing rodent diet for 4 weeks. Systolic blood pressure (SBP) and urine NaCl excretion were measured weekly, and kidneys were harvested for immunoblotting and quantitative PCR analysis at the end of the animal experiments. Results: SBP was significantly higher in SS rats than in SR rats during the first to fourth weeks of the animal experiments. During the first and second week, urinary NaCl excretion was significantly lower in SS rats as compared with SR rats. However, the difference between the two groups vanished at the third and fourth weeks. In the kidney, claudin-4 protein and mRNA were significantly increased in SS rats as compared with SR rats. On the other hand, occludin protein and mRNA were significantly decreased in SS rats as compared with SR rats. The expression of claudin-2, claudin-7, and claudin-8 did not vary significantly between the two groups. Conclusions: In SS rats, SS hypertension was associated with differential changes in renal TJ protein expression. Both upregulation of claudin-4 and downregulation of occludin might increase paracellular NaCl transport in the kidney, resulting in impaired pressure natriuresis in SS rats.

OS 21-04 UPREGULATION OF CLAUDIN-4 IN THE KIDNEY OF DAHL SALT-SENSITIVE RATS

Objective: Claudins are tight junction proteins that regulate paracellular permeability of renal epithelia, and renal paracellular sodium chloride permeability may be essential to salt homeostasis and blood pressure control. A previous study has shown that the collecting duct-specific claudin-4 knockout animals develop hypotension due to profound renal wasting of chloride. This study was undertaken to investigate whether claudins have a role in the hypertension of Dahl salt-sensitive (DS) rats. Design and Method: Male DS and Dahl salt-resistant (DR) rats, 6 of each, were maintained on an 8% NaCl-containing rodent diet for 4 weeks. Systolic blood pressure (SBP) and plasma and urine electrolytes were weekly measured. At the end of animal experiment, kidneys were harvested for immunoblotting and quantitative PCR analysis of tight junction proteins including claudin-2, claudin-4, claudin-7, claudin-8, occludin, and ZO-1. Results: SBP was significantly higher in DS than in DR rats at the 1st to 4th week of the animal experiment. At the 1st and 2nd week, urine sodium and chloride excretion were significantly reduced in DS as compared with DR rats. At the 2nd week, DS rats had lower concentrations of plasma sodium and chloride than DR rats. The body weight measured at the end of animal experiment was lower in DS than in DR rats. In the kidney, claudin-4 protein and mRNA were significantly increased in DS as compared with DR rats. On the other hand, occludin protein and mRNA were significantly decreased in DS as compared with DR rats. The expressions of claudin-2, claudin-7, and claudin-8 were not significantly different between the two groups. Conclusions: In DS rats, salt-sensitive hypertension was associated with differential changes in renal tight junction protein expression. Upregulation of claudin-4 might increase paracellular sodium chloride transport in the kidney, resulting in impaired pressure natriuresis in DS rats.

Mathematical Model‐based Analysis of the Acute and Chronic Mechanisms of Diabetic Hyperfiltration

An increase in glomerular filtration rate (GFR) in early diabetes has been associated with development and progression of diabetic kidney disease. Our understanding of the mechanisms responsible for hyperfiltration and subsequent renal injury is incomplete, but may be critical for developing new approaches to prevent diabetic kidney disease. The tubular hypothesis of hyperfiltration proposes that hyperfiltration is initiated by a primary increase in sodium (Na) reabsorption in the proximal tubule (PT), due to tubular growth and increased Na‐glucose cotransport.The renal response to a primary increase in PT Na reabsorption likely involves multiple mechanisms over both the acute and chronic timescales. A more complete understanding of the relative contributions of the driving mechanisms, as well as the relationship between the acute and chronic response, is needed to better understand how diabetic hyperfiltration is initiated and maintained. In this study, we utilized an integrated mathematical model of the renal vasculature, tubular Na and fluid handling, and systemic blood volume regulation to investigate the mechanisms responsible for the hyperfiltration response to increased Na reabsorption in the PT.We find that both tubuloglomerular feedback (TGF) and decreased PT pressure likely contribute to the acute GFR response to increased PT reabsorption. However, these mechanisms and the acute GFR rise appear insufficient to fully return Na balance. Additional adaptations must occur chronically to restore Na balance – either distal Na reabsorption must be reduced to compensate for the increased PT reabsorption, or GFR must be further augmented to match Na excretion to intake. We find that when preglomerular autoregulation is intact, modest distal reductions in Na reabsorption can fully compensate, with no further increase in GFR needed. The distal effect is driven by true pressure‐natriuresis, but regulation by renal sympathetic nerve activity and the renin angiotensin aldosterone system moderate this effect and allow Na homeostasis with minimal increases in blood pressure. However, when preglomerular autoregulation or downregulation of distal Na reabsorption is impaired (as has been proposed in diabetes), Na balance is returned through a further increase in glomerular pressure/GFR.In summary, these results suggest that the hyperfiltration response to a primary increase in PT Na reabsorption is multifactorial. While the acute response is likely dominated by TGF and tubular pressure changes, impaired renal autoregulation and impaired pressure natriuresis/ neurohumoral distal Na transport regulation contribute to the magnitude of the chronic hyperfiltration response and the associated increase in glomerular pressure. In other words, improving preglomerular autoregulation and/or restoring renal Na transport regulation may attenuate hyperfiltration/glomerular hypertension and thereby the drive to renal damage long‐term. An interactive interface to the model is available at qsp.engr.uga.edu:3838/Hyperfiltration_EB.

Renal Dysfunction, Rather Than Nonrenal Vascular Dysfunction, Mediates Salt-Induced Hypertension.

Chronic excess salt intake increases the risk for hypertension and moderation of salt intake is an important strategy for prevention of cardiovascular and kidney disease, especially in salt-sensitive subjects. Although short-term blood pressure (BP) responses to high salt intake over several days are highly variable, chronic high salt intake worsens BP salt-sensitivity. Aging, diabetes, hypertension, and various acquired and genetic kidney disorders also exacerbate salt-sensitivity of BP. Kidney dysfunction, characterized by impaired pressure natriuresis, has been demonstrated in all forms of experimental and human genetic or acquired salt-sensitive hypertension studied thus far. Abnormalities of kidney function that directly or indirectly increase NaCl reabsorption, decrease glomerular capillary filtration coefficient, or cause nephron injury/loss exacerbate BP salt-sensitivity. In most cases, salt-sensitive hypertension is effectively treated with drugs that increase glomerular filtration rate or reduce renal NaCl reabsorption (e.g. diuretics, renin-angiotensin-aldosterone system blockers). Increased vascular resistance may occur concomitantly or secondarily to kidney dysfunction and increased BP in salt-sensitive hypertension. However, primary increases in non-renal vascular resistance have not been shown to cause salt-sensitive hypertension or long-term changes in BP in the absence of impaired renal-pressure natriuresis. The mechanisms responsible for increased total peripheral resistance (TPR) during high salt intake in salt-sensitive subjects are not fully understood but likely involve pressure-dependent and/or flow-dependent autoregulation in peripheral tissues as well as neurohormonal factors that occur concomitantly with kidney dysfunction. Physiological studies have demonstrated that increased BP almost invariably initiates secondary pressure-dependent functional and structural vascular changes that increase TPR.

Abstract P167: Conditional Deletion of the Na+/H+ Exchanger 3 in the Proximal Tubule of the Kidney Promotes Pressure Natriuresis in Mice

The development and progression of most, if not all, forms of hypertension appear to converge on a final common pathway or mechanism, i.e., increased renal salt retention due to significantly impaired pressure natriuresis responses. Yet the factors responsible for resetting the pressure natriuresis response in hypertension remain to be determined. The present study tested the hypothesis that the upregulation of the sodium and hydrogen exchanger 3 (NHE3) impairs while selective knockout of this transporter in the proximal tubule promotes pressure natriuresis and lowers blood pressure in mice. Proximal tubule-specific NHE3 knockout mice (PT-NHE3-KO) were generated by the Cre/Lox approach, and confirmed by complementary PCR, Western blot, and immunofluorescent imaging of NHE3 expression in the proximal tubule of the kidney, respectively. No abnormal histological phenotypes were observed in small intestines and the kidney of PT-NHE3-KO mice. Compared with wild-type mice (WT, n=12), PT-NHE3-KO mice (n=10) had significantly lower basal systolic blood pressure (WT: 116 ± 3 mmHg versus PT-NHE3-KO: 103 ± 3 mmHg, p<0.01). Mean intra-arterial pressure was also significantly lower in anesthetized PT-NHE3-KO mice (WT: 91 ± 3 mmHg versus PT-NHE3-KO: 77 ± 5 mmHg, p<0.01) (n=8 each). The lower basal blood pressure in PT-NHE3-KO mice was associated with higher basal urine flow (WT: 0.81 ± 0.09 ml/day versus PT-NHE3-KO: 1.12 ± 0.06 ml/day, p<0.05), urinary sodium (WT: 120.1 ± 17.5 μmol/day versus PT-NHE3-KO: 197.1 ± 24.5 μmol/day, p<0.01), potassium (WT: 171.7 ± 26.0 μmol/day versus PT-NHE3-KO: 310.3 ± 24.3 μmol/day, p<0.01), and chloride excretion (WT: 125.7 ± 22.5 μmol/day versus PT-NHE3-KO: 222 ± 29.2 μmol/day, p<0.05) (n=8-12 for each group). In response to ~25 mmHg increase in renal perfusion pressure in both strains, urinary sodium excretion was increased by 4-fold in WT mice (n=12, p<0.01), whereas it increased by 7-fold in PT-NHE3-KO mice (n=10, p<0.01). We concluded that NHE3 in the proximal tubule of the kidney plays an important role in the regulation of proximal tubular sodium reabsorption and blood pressure homeostasis, and that selective deletion of NHE3 in the proximal tubule promotes the pressure natriurestic response and lowers blood pressure in mice.

The immunological basis of hypertension.

A large number of investigations have demonstrated the participation of the immune system in the pathogenesis of hypertension. Studies focusing on macrophages and Toll-like receptors have documented involvement of the innate immunity. The requirements of antigen presentation and co-stimulation, the critical importance of T cell-driven inflammation, and the demonstration, in specific conditions, of agonistic antibodies directed to angiotensin II type 1 receptors and adrenergic receptors support the role of acquired immunity. Experimental findings support the concept that the balance between T cell-induced inflammation and T cell suppressor responses is critical for the regulation of blood pressure levels. Expression of neoantigens in response to inflammation, as well as surfacing of intracellular immunogenic proteins, such as heat shock proteins, could be responsible for autoimmune reactivity in the kidney, arteries, and central nervous system. Persisting, low-grade inflammation in these target organs may lead to impaired pressure natriuresis, an increase in sympathetic activity, and vascular endothelial dysfunction that may be the cause of chronic elevation of blood pressure in essential hypertension.

Loss of Collectrin, an Angiotensin-Converting Enzyme 2 Homolog, Uncouples Endothelial Nitric Oxide Synthase and Causes Hypertension and Vascular Dysfunction

Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after subtotal nephrectomy and during high-salt feeding, raising the question of whether collectrin has any direct role in blood pressure regulation. Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity, and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelium-dependent vasorelaxation that is associated with vascular remodeling, endothelial nitric oxide synthase uncoupling, decreased nitric oxide production, and increased superoxide generation. Treatment with Tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates l-arginine uptake and plasma membrane levels of CAT1 and y(+)LAT1 amino acid transporters in endothelial cells. Treatment with l-arginine modestly lowers blood pressure of collectrin knockout mice. Collectrin is a consequential link between the transport of l-arginine and endothelial nitric oxide synthase uncoupling in hypertension.

Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney

Immune cell infiltration of the kidney is a constant feature in salt-sensitive hypertension (SSHTN). We evaluated the relationship between the renal inflammation and pressure natriuresis in the model of SSHTN that results from transient oral administration of N(ω)-nitro-L-arginine methyl ester (L-NAME). Pressure natriuresis was determined in Wistar rats that received 4 wk of a high-salt (4% NaCl) diet, starting 1 wk after stopping L-NAME, which was administered alone (SSHTN group, n = 17) or in association with mycophenolate mofetil (MMF; MMF group, n = 15). The administration of MMF in association with L-NAME is known to prevent the subsequent development of SSHTN. Control groups received a high (n = 12)- and normal (0.4%)-salt diet (n = 20). Rats with SSHTN had increased expression of inflammatory cytokines and oxidative stress. The severity of hypertension correlated directly (P < 0.0001) with the number of tubulointerstitial immune cells and angiotensin II-expressing cells. Pressure natriuresis was studied at renal arterial pressures (RAPs) of 90, 110, 130, and 150 mmHg. Glomerular filtration rate was similar and stable in all groups, and renal blood flow was decreased in the SSHTN group. Significantly decreased natriuresis (P < 0.05) was found in the SSHTN group at RAPs of 130 and 150 mmHg, and there was an inverse correlation (P < 0.01) between the urinary sodium excretion and the number of tubulointerstitial inflammatory cells (lymphocytes and macrophages) and cells expressing angiotensin II. We conclude that tubulointerstitial inflammation plays a key role in the impairment of pressure natriuresis that results in salt-dependent hypertension in this experimental model.

Impaired pressure natriuresis is associated with interstitial inflammation in salt-sensitive hypertension

Impairment of the pressure natriuresis relationship is a central event in the pathogenesis of hypertension. Renal tubulointerstitial inflammation results in salt-sensitive hypertension and, until recently, the changes in pressure natriuresis induced by renal inflammation received little attention. Oxidative stress and increased intrarenal angiotensin II activity, in association with rarefaction and loss of peritubular vascular network, may be involved in the inflammation-induced blunting of the natriuresis resulting from increments in renal perfusion pressure. Here, we review the mechanisms for the impairment in pressure natriuresis resulting from renal tubulointerstitial inflammation in reference to the normal physiologic mechanisms involved in this response.

ATP Releasing Connexin 30 Hemichannels Mediate Flow-Induced Calcium Signaling in the Collecting Duct

ATP in the renal tubular fluid is an important regulator of salt and water reabsorption via purinergic calcium signaling that involves the P2Y2 receptor, ENaC, and AQP2. Recently, we have shown that connexin (Cx) 30 hemichannels are localized to the non-junctional apical membrane of cells in the distal nephron-collecting duct (CD) and release ATP into the tubular fluid upon mechanical stimuli, leading to reduced salt and water reabsorption. Cx30−/− mice show salt-dependent elevations in BP and impaired pressure-natriuresis. Thus, we hypothesized that increased tubular flow rate leads to Cx30-dependent purinergic intracellular calcium ([Ca2+]i) signaling in the CD. Cortical CDs (CCDs) from wild type and Cx30−/− mice were freshly dissected and microperfused in vitro. Using confocal fluorescence imaging and the calcium-sensitive fluorophore pair Fluo-4 and Fura Red, we found that increasing tubular flow rate from 2 to 20 nl/min caused a significant 2.1-fold elevation in [Ca2+]i in wild type CCDs. This response was blunted in Cx30−/− CCDs ([Ca2+]i increased only 1.2-fold, p < 0.0001 vs. WT, n = 6 each). To further test our hypothesis we performed CD [Ca2+]i imaging in intact mouse kidneys in vivo using multiphoton microscopy and micropuncture delivery of the calcium-sensitive fluorophore Rhod-2. We found intrinsic, spontaneous [Ca2+]i oscillations in free-flowing CDs of wild type but not Cx30−/− mice. The [Ca2+]i oscillations were sensitive also to P2-receptor inhibition by suramin. Taken together, these data confirm that mechanosensitive Cx30 hemichannels mediate tubular ATP release and purinergic calcium signaling in the CD which mechanism plays an important role in the regulation of CD salt and water reabsorption.

AT2 receptor: Its role in obesity associated hypertension.

The renin-angiotensin system (RAS) is a hormonal cascade that acts together to regulate blood pressure. Angiotensin II (Ang II) is the major octapeptide of RAS and mediates its cellular and physiological actions by acting on AT1 and AT2 receptor. Most of the cellular and physiological actions of Ang II such as cellular growth and proliferation, vasoconstriction, antinatriuresis and increase in blood pressure are mediated via AT1 receptor. The functions associated with the AT2 receptors are less studied, in part, due to its lower expression in adult tissues. However, AT2 receptor has been suggested as functional antagonist of AT1 receptors and thereby opposes the actions of Ang II mediated via AT1 receptor. Thus, the activation of AT2 receptors has been shown to cause vasodilatation, natriuresis and decrease in blood pressure. After the discovery of the AT2 receptor in various parts of the kidney, including in proximal tubules, there has been an interest in establishing a link between the renal AT2 receptor, renal Na-excretion and blood pressure regulation. Earlier, we have reported that activation of renal AT2 receptors increases urinary Na excretion in obese Zucker rats, in part via inhibiting Na+/K+- ATPase (NKA) activity and stimulating nitric oxide/cGMP pathway in the proximal tubules. An impaired pressure natriuresis and increased AT1 receptor function is believed to be the cause of hypertension in obese Zucker rats and other animal models of obesity. In this review, we are focussing on the role of renin angiotensin system especially AT2 receptors in obesity associated hypertension.

Abstract 90: Loss of Collectrin Augments Salt-sensitivity and Alters Nitric Oxide and Superoxide Balance.

Collectrin, an ACE-2 homologue, plays a major role in amino acid transport in renal epithelial cells. In the rodent kidney, the expression of collectrin is upregulated after reduction of nephron mass and during salt-sensitive hypertension. These observations raise the question of how collectrin might be functionally integrated in the ACE family in the context of blood pressure (BP) regulation. We previously reported that, on a susceptible genetic background, collectrin-deficient (KO) mice have elevated baseline systolic blood pressure (SBP) and impaired endothelium-dependent relaxation (EDR) of thoracodorsal arteries (TDA). Treatment with L-NAME, a nitric oxide synthase (NOS) inhibitor, normalized their BP and EDR of TDA. Here, to determine whether collectrin plays a role in salt-sensitivity (SS), we fed mice a high salt diet (HSD) for 2 weeks. By radiotelemetry, KO mice displayed augmented salt-sensitivity (SS) (Normal salt (NS): Wild-type (WT) 133 ± 1 mm Hg, KO 141 ± 3 mm Hg; HSD: WT 141 ± 2 mm Hg, KO 155 ± 3 mm Hg; change in SBP: WT 7.8 ± 1.4 mm Hg, KO 14.4 ± 1.5 mm Hg; p ≤ 0.02), and lower urinary sodium excretion (UNa) during the first 3 days of HSD (mean UNa over 3 days: KO: 1980 ± 193 μmol/24h, WT: 2650 ± 98 μmol/24h, p = 0.006, ANOVA; n ≥ 6). The impaired pressure natriuresis in KO mice was associated with altered urinary excretion of 8-isoprostane F 2 α (WT 3.0 ± 0.67 ng/mg, KO 7.7 ± 1.5 ng/mg creatinine, p = 0.008) and nitrates/nitrites (WT 10.2 ± 1.4 nmol/day, KO 6.2 ± 0.61 nmol/day, p = 0.03, n ≥ 4 each). We previously reported that KO mice have increased state of endothelial NOS (eNOS) uncoupling. Here, by immunostaining, we found that collectrin is expressed in endothelial cells (ECs). We next queried whether collectrin affects L-arginine (L-Arg) transport in ECs. After isolation from the pulmonary artery, primary ECs from KO mice displayed impaired [ 3 H]L-Arg uptake (WT 2.00 ± 0.19, KO 0.90 ± 0.06 pmol/mg protein/min, p=0.01) To establish direct cause and effect, we over-expressed collectrin in primary human coronary ECs which resulted in increased [ 3 H]L-Arg uptake (Control 4.20 ± 0.32; Overexpression 6.60 ± 0.59 pmol/mg protein/min, p &lt; 0.003). In conclusion, collectrin may regulate BP and SS by modulating the balance of NO and SO through its role in L-Arg transport in ECs.

Distinct effects on long-term function of injured and contralateral kidneys following unilateral renal ischemia-reperfusion

Salt-sensitive hypertension and chronic kidney disease (CKD) following recovery from acute kidney injury (AKI) may occur secondary to incomplete repair, or by activation of circulating factors stimulated by injury. We created two types of renal injury induced by unilateral ischemia-reperfusion (I/R); in a direct/ipsilateral AKI group, rats were subjected to unilateral I/R and the untouched contralateral kidney was removed by unilateral nephrectomy after 5 wk to isolate effects on the injured kidney. In the remote/contralateral AKI group, the injured kidney was removed after 5 wk to isolate effects on the untouched kidney. When these animals were subsequently challenged with elevated dietary sodium for an additional 4 wk (0.4 to 4%), both remote/contralateral and direct/ipsilateral AKI rats manifested a significant increase in blood pressure relative to sham-operated controls. Similarly, in acute studies, both ipsilateral and contralateral kidneys had impaired pressure natriuresis and hemodynamic responses. Reductions in vascular density were observed following direct/ipsilateral injury, but were not observed in the remote/contralateral kidney. However, both remote/contralateral and direct/ipsilateral kidneys contained interstitial cells, some of which were identified as activated (low CD62L/CD4+) T lymphocytes. In contrast, only the direct/ipsilateral AKI group demonstrated significant CKD following exposure to elevated salt. This was characterized by a significant reduction in creatinine clearance, an increase in albuminuria, and a dramatic expansion of interstitial inflammation. Taken together, these data suggest that the salt-sensitive features of AKI on hypertension and CKD are segregable such that effects on hemodynamics and hypertension occur independent of direct renal damage. However, prior direct injury to the kidney is required to elicit the full manifestation of CKD induced by elevated sodium intake.

Fat Chance for Hypertension and Chronic Kidney Disease

See related article, pp 784–790 Obesity is firmly associated with both hypertension and chronic kidney disease (CKD). Although these areas have been the subject of intense investigation over the last 2 decades, the mechanisms and best clinical indicators are not fully resolved. In the current issue, Foster et al1 provide intriguing evidence associating increased renal sinus fat (“fatty kidney”) specifically with increased prevalence of hypertension and CKD. The prevalence of obesity continues to increase globally, as has occurred over the last few decades. Obesity has been definitively linked to hypertension and other cardiovascular diseases for many years. Numerous animal models and human studies have explored the mechanisms linking obesity to hypertension. Several factors have been consistently shown with obesity (Figure): increased sympathetic nervous system activity, increased renin-angiotensin-aldosterone system activity, and increased sodium reabsorption (and/or impaired pressure natriuresis) among other mechanisms.2,3 A variety of adipocyte-derived factors, such as leptin, have also been shown to be involved. In addition, local or systemic inflammatory cascades, endothelial dysfunction, and reactive oxygen species likely have a role in the mechanistic links between obesity and hypertension. Figure. Speculative diagram of the relationships between aspects of obesity, hypertension (HTN), and chronic kidney disease (CKD). Generalized obesity, abdominal (or visceral) obesity, and fatty kidney largely overlap but may have distinct mechanistic links …

Inhibition of soluble epoxide hydrolase improves the impaired pressure–natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats

In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure-natriuresis relationship in response to stepwise reduction in renal arterial pressure (RAP) in Cyp1a1-Ren-2 transgenic rats. Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration for 11 days of the natural xenobiotic indole-3-carbinol (I3C) which activates the renin gene. Treatment with c-AUCB and losartan was started 48 h before initiating administration of the diet containing I3C. Rats were prepared for renal functional studies to evaluate in-vivo renal autoregulatory efficiency when RAP was gradually decreased by an aortic clamp. I3C administration resulted in the development of severe hypertension which was associated with markedly lower basal RBF and GFR and substantially impaired autoregulatory efficiency as well as a suppression of the pressure-natriuresis relationship when compared with noninduced rats. Treatment with c-AUCB significantly decreased BP, improved autoregulatory efficiency of RBF and GFR and the slope of pressure-natriuresis relationship. Treatment with losartan completely prevented the impaired autoregulation and pressure-natriuresis relationship as well as the development of hypertension in I3C-induced rats. Our present findings indicate that chronic treatment with the sEH inhibitor c-AUCB substantially attenuates the development of malignant hypertension in I3C-induced rats likely via improvement of the renal autoregulatory efficiency and the pressure-natriuresis relationship.

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

Primary (essential) hypertension has been shown to be mediated by a relative impairment in sodium excretion by the kidney, but the mechanisms responsible for this defect are still being clarified. Increasing evidence suggests a role for subtle acquired renal injury in mediating this process. Microvascular injury is present in the majority of subjects with hypertension. The development of arteriolosclerosis, primarily of the afferent arteriole, may interfere with glomerular autoregulation, whereas the loss of peritubular capillaries may facilitate local ischemia. These changes favor the localization of T cells and macrophages into the interstitium, which, coupled with local oxidative stress and angiotensin II generation, may contribute to the impaired pressure natriuresis observed with salt-sensitive hypertension. Consistent with this hypothesis, therapies that are aimed at blocking the immune response, including thymectomy, genetic alterations in mice resulting in impaired immune responses, or the use of immunosuppressive agents, can protect against the development of hypertension in experimental models. Preliminary data in humans also suggest that the inhibition of the renal inflammatory response may reduce blood pressure. The present investigations are directed to gain insight in the role of the intrarenal T-cell reactivity and autoimmunity in driving the tubulointerstitial inflammation and its participation in the pathogenesis of salt-sensitive hypertension.