Glomerular Capillary Pressure Research Articles

Salt sensitivity and circadian rhythm of blood pressure: the keys to connect CKD with cardiovasucular events

In healthy subjects, blood pressure (BP) drops by 10-20% during the night. Conversely, in patients with the salt-sensitive type of hypertension or chronic kidney disease, nighttime BP does not fall, resulting in an atypical pattern of circadian BP rhythm that does not dip. This pattern is referred to as the 'non-dipper' pattern. Loss of renal functional reserve, due to either reduced ultrafiltration capacity or enhanced tubular sodium reabsorption, induces the salt-sensitive type of hypertension. When salt intake is excessive in patients with salt-sensitive hypertension, the defect in sodium excretory capability becomes evident, resulting in elevated BP during the night. This nocturnal hypertension compensates for diminished natriuresis during the daytime and enhances pressure natriuresis during the night. Nocturnal hypertension and the non-dipper pattern of circadian BP rhythm cause cardiovascular events. When excess salt intake is loaded in patients who are in a salt-sensitive state, glomerular capillary pressure is also elevated, resulting in glomerular sclerosis and eventual renal failure. In this way, salt sensitivity and excess salt intake contribute to both cardiovascular and renal damage at the same time. We propose that salt sensitivity of BP and excess salt intake have important roles in the genesis of the cardiorenal connection. Salt sensitivity and circadian rhythm of BP are the keys to understanding the connections between cardiovascular and renal complications.

Enhanced myogenic response in the afferent arteriole of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHRs) have normal glomerular capillary pressure even though renal perfusion pressure is higher, suggesting that preglomerular vessels exhibit abnormally high resistance. This may be due to increased superoxide (O(2)(-)) production, which contributes to the vasoconstriction in hypertension. We tested the hypothesis that the myogenic response of the afferent arteriole (Af-Art) is exaggerated in SHRs because of increased levels of reactive oxygen species (ROS). Single Af-Arts were microdissected from kidneys of SHRs and Wistar-Kyoto (WKY) rats and microperfused in vitro. When perfusion pressure in the Af-Art was increased stepwise from 60 to 140 mmHg, the luminal diameter decreased by 8.4 + or - 2.9% in WKY Af-Arts but fell by 29.3 + or - 5.6% in SHR Af-Arts. To test whether ROS production is enhanced during myogenic response in SHRs, we measured chloromethyl-dichlorodihydrofluorescein diacetate acetyl ester (CM-H(2)DCFDA) florescence before and after increasing intraluminal pressure from 60 to 140 mmHg. Pressure-induced increases in ROS were fourfold greater in SHR Af-Arts compared with WKY Af-Arts (SHR, 48.0 + or - 2.2%; and WKY, 12.2 + or - 0.3%). To test whether O(2)(-) contributes to the myogenic response in SHRs, either the membrane-permeant O(2)(-) scavenger Tempol or the nox2-based NADPH oxidase (NOX2) inhibitor gp91ds-tat were added to the Af-Art lumen and bath and the myogenic response was tested before and after treatment. Both Tempol (10(-4) M) and gp91ds-tat (10(-5) M) significantly attenuated the pressure-induced constriction in SHR Af-Arts but not in WKY Af-Arts. We conclude that 1) pressure-induced constriction is exaggerated in SHR Af-Arts, 2) NOX2-derived O(2)(-) may contribute to the enhanced myogenic response, and 3) O(2)(-) exerts little influence on the myogenic response under normotensive conditions.

Mechanical stretch and prostaglandin E 2 modulate critical signaling pathways in mouse podocytes

Elevated glomerular capillary pressure (Pgc) and hyperglycemia contribute to glomerular filtration barrier injury observed in diabetic nephropathy (DN). Previous studies showed that hypertensive conditions alone or in combination with a diabetic milieu impact podocyte cellular function which results in podocyte death, detachment or hypertrophy. The present study was aimed at uncovering the initial signaling profile activated by Pgc (mimicked by in vitro mechanical stretch), hyperglycemia (high glucose (HG), 25 mM d-glucose) and prostaglandin E 2 (PGE 2) in conditionally-immortalized mouse podocytes. PGE 2 significantly reduced the active form of AKT by selectively blunting its phosphorylation on S473, but not on T308. AKT inhibition by PGE 2 was reversed following either siRNA-mediated EP 4 knockdown, PKA inhibition (H89), or phosphatase inhibition (orthovanadate). Podocytes treated for 20 min with H 2O 2 (10 − 4 M), which mimics reactive oxygen species generation by cells challenged by hyperglycemic or enhanced Pgc conditions, significantly increased the levels of active p38 MAPK, AKT, JNK and ERK1/2. Interestingly, stretch and PGE 2 each significantly reduced H 2O 2-mediated AKT phosphorylation and was reversed by pretreatment with orthovanadate while stretch alone reduced GSK-3β inhibitory phosphorylation at ser-9. Finally, mechanical stretch alone or in combination with HG, induced ERK1/2 and JNK activation, via the EGF receptor since AG1478, a specific EGF receptor kinase inhibitor, blocked this activation. These results show that cellular signaling in podocytes is significantly altered under diabetic conditions (i.e., hyperglycemia and increased Pgc). These changes in MAPKs and AKT activities might impact cellular integrity required for a functional glomerular filtration barrier thereby contributing to the onset of proteinuria in DN.

T-Type Ca Channel Blockade as a Determinant of Kidney Protection

Voltage-dependent Ca channels are classified into several subtypes based on the isoform of their α1 subunits. Traditional Ca channels blockers (CCBs), including nifedipine and amlodipine, act predominantly on L-type Ca channels, whereas novel CCBs such as efonidipine, benidipine and azelnidipine inhibit both L-type and T-type Ca channels. Furthermore, cilnidipine blocks L-type and N-type Ca channels. These CCBs exert divergent actions on renal microvessels. L-type CCBs preferentially dilate afferent arterioles, whereas both L-/T-type and L-/N-type CCBs potently dilate afferent and efferent arterioles. The distinct actions of CCBs on the renal microcirculation are reflected by changes in glomerular capillary pressure and subsequent renal injury: L-type CCBs favor an increase in glomerular capillary pressure, whereas L-/T-type and L-/N-type CCBs alleviate glomerular hypertension. The renal protective action of L-/T-type CCBs is also mediated by non-hemodynamic mechanisms, i.e., inhibition of the inflammatory process and inhibition of Rho kinase and aldosterone secretion. Finally, a growing body of evidence indicates that T-type CCBs offer more beneficial action on proteinuria and renal survival rate than L-type CCBs in patients with chronic kidney disease (CKD). Similarly, in CKD patients treated with renin-angiotensin blockers, add-on therapy with N-type CCBs is more potent in reducing proteinuria than that with L-type CCBs, although no difference is found in the subgroup with diabetic nephropathy. Thus, the strategy for hypertension treatment with CCBs has entered a new era: treatment selection depends not only on blood pressure control but also on the subtypes of CCBs.

Calcium antagonists: current and future applications based on new evidence. Renal protective action of calcium channel blockers

Ca channel blockers have been widely prescribed as an antihypertensive agent in Japan, because the blood pressure (BP) lowering effect of it is strong among Japanese patients whose amount of salt intake is high and patients with chronic kidney disease (CKD) whose sodium sensitivity of BP is enhanced. In addition, it can maintain the perfusion pressure into important organs including kidneys despite lowered systemic BP, and can be used efficiently in combinations with many types of antihypertensive agents. On the other hand, most of Ca channel blockers dilate mainly preglomerular afferent arterioles, resulting in elevated glomerular capillary pressure. Therefore, renal protection by Ca channel blockers remains in debate. We will discuss the renal protective action of new Ca channel blockers, which can dilate postglomerular efferent arterioles.

Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits

Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5'-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease.

Change of Glomerular Hemodynamics in Patients with Advanced Chronic Kidney Disease after Cilnidipine Therapy

Cilnidipine, a dual calcium channel antagonist, is assumed to regulate hypertension via N- and L-type calcium channel. The N-type calcium channel is associated with sympathetic nerve activation. This effect may improve the glome- rular hemodynamics in the injured nephron, and may mitigate the progression of renal injury. To clarify the effect of cil- nidipine in instances of already existing decreased renal blood flow, we examined the alteration of renal hemodynamics before and after cilnidipine therapy in patients with advanced chronic kidney disease (CKD). Cilnidipine was adminis- trated daily to 17 CKD patients with hypertension for 12 months. Another 16 patients were similarly administered am- lodipine during this study, a long-acting L-type calcium channel antagonist has also been shown to be renoprotective. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and protein excretion in 24-hour accumulated urine were measured at the start and end of the study. The parameters of renal hemodynamics were calculated by Gomez's es- timation equation. Systolic blood pressure decreased to 80 % of the level at the beginning of the study, and ERPF in- creased to 127 % of the level at baseline. Glomerular capillary pressure on single nephron was reduced to 90 %, although total GFR decreased within the non-statistical change. Especially, renal vascular resistance ratio (RA/RE) on single neph- ron improved to 120 %. Cilnidipine improves ERPF and glomerular hypertension without worsening total renal function. N- and L-type calcium channel antagonist is effective and safe for patients with advanced CKD as a result of improve- ment of glomerular capillary resistance.

Diurnal Changes in Urinary Excretion of IgG, Transferrin, and Ceruloplasmin Depend on Diurnal Changes in Systemic Blood Pressure in Normotensive, Normoalbuminuric Type 2 Diabetic Patients

Previous studies of diabetic patients indicate that increased urinary excretion of certain plasma proteins (molecular radii <55 A), such as IgG, transferrin, and ceruloplasmin, precede the development of microalbuminuria. Moreover, increases in these urinary proteins predict future development of microalbuminuria. To clarify whether blood pressure changes influence urinary excretion of these proteins, we examined relationships between diurnal blood pressure changes measured by ambulatory blood pressure monitoring and urinary excretion of IgG, transferrin, ceruloplasmin, alpha2-macroglobulin (88 A) and albumin (36 A) measured separately during the day and night in 20 healthy controls and 26 normotensive, normoalbuminuric diabetic patients. Diurnal change in systolic blood pressure was not correlated to urinary excretion of either albumin or alpha2-macroglobulin in either diabetic patients or controls. However, statistically significant correlations between diurnal changes in systolic blood pressure and those of urinary excretion of IgG, transferrin and ceruloplasmin were found in diabetic patients but not in controls. The present findings suggest that urinary excretion of IgG, transferrin, and ceruloplasmin are more easily affected than albuminuria by systemic blood pressure changes in normoalbuminuric diabetic patients. This is supported by our previous finding that urinary excretion of IgG, transferrin and ceruloplasmin increased while albuminuria did not following enhanced glomerular filtration rate after acute protein loading, which causes increased glomerular capillary pressure due to afferent arterioles dilation, mimicking diabetic intra-renal hemodynamics. Taken together, these findings suggest that urinary excretion of IgG, transferrin, and ceruloplasmin may be more sensitive indicators of glomerular capillary pressure change than albuminuria in normoalbuminuric diabetic patients.

Salt-resistant blood pressure and salt-sensitive renal autoregulation in chronic streptozotocin diabetes

Hyperfiltration occurs in early type 1 diabetes mellitus in both rats and humans. It results from afferent vasodilation and thus may impair stabilization of glomerular capillary pressure by autoregulation. It is inversely related to dietary salt intake, the "salt paradox." Restoration of normal glomerular filtration rate (GFR) involves increased preglomerular resistance, probably mediated by tubuloglomerular feedback (TGF). To begin to test whether the salt paradox has pathogenic significance, we compared intact vs. diabetic (streptozotocin) Long-Evans rats with normal and increased salt intake, 1 and approximately 3% by weight of food eaten, respectively. Weekly 24-h blood pressure records were acquired by telemetry before and during diabetes. Blood glucose was maintained at approximately 20 mmol/l by insulin implants. GFR was significantly elevated only in diabetic rats on normal salt intake, confirming diabetic hyperfiltration and the salt paradox. Renal blood flow dynamics show strong contributions to autoregulation by both TGF and the myogenic mechanism and were not impaired by diabetes or by increased salt intake. Separately, systolic pressure was not elevated in diabetic rats at any time during 12 wk with normal or high salt intake. Autoregulation was effective in all groups, and the diabetic-normal salt group showed significantly improved autoregulation at low perfusion pressures. Histological examination revealed very minor glomerulosclerosis and modest mesangial expansion, although neither was diagnostic of diabetes. Periodic acid-Schiff-positive droplets found in distal tubules and collecting duct segments were diagnostic of diabetic kidneys. Biologically significant effects attributable to increased salt intake were abrogation of hyperfiltration and of the left shift in autoregulation in diabetic rats.

Independent two-photon measurements of albumin GSC give low values

Independent two-photon measurements of albumin GSC give low values

Abnormal autoregulation and tubuloglomerular feedback in prediabetic and diabetic OLETF rats

The mechanisms underlying the development and prevention of diabetic nephropathy are still not fully understood. In the present study in the Otsuka Long-Evans Tokushima Fatty (OLETF) model of type 2 diabetic rats, we investigated whether renal hemodynamic abnormalities exist and whether they precede the onset of diabetes. Using OLETF rats in both prediabetic and diabetic stages, we assessed autoregulatory responses of total renal blood flow (RBF) and of superficial (SBF) and deep renal cortical (DBF) blood flow to stepwise reductions of renal perfusion pressure (RPP) induced by a manual clamp on the abdominal aorta. During clamp-induced reductions of RPP by 10 or 20 mmHg, RBF fell significantly more in OLETF rats than in lean control [Long-Evans Tokushima Otsuka (LETO)] rats. Whereas SBF showed no significant changes in either OLETF rats or LETO rats during mild clamping, DBF decreased significantly more in OLETF rats than LETO rats. Reduced autoregulatory efficiency in OLETF rats was observed in both prediabetic and diabetic stages. Micropuncture studies showed that tubuloglomerular feedback (TGF) responses of stop flow pressure are reduced in prediabetic (-7.3 vs. -25.7%) as well as in diabetic OLETF rats compared with LETO control rats (-4.4 vs. -18.8%). Renal corticotomy was performed to measure glomerular capillary pressure (Pgc) directly. Pgc of deep cortical glomeruli was higher than superficial glomerular Pgc in both strains of rats, but the difference was especially pronounced in OLETF rats (deep 78 +/- 2 vs. superficial 57 +/- 4 mmHg). This study demonstrates reduced autoregulatory adjustments and impaired TGF efficiency in prediabetic OLETF rats. Thus abnormal RBF regulation precedes the onset of diabetes and is especially pronounced in the deep cortical region.

Mysteries of Renal Autoregulation

Autoregulation is an important renal regulatory mechanism that provides an important protective role in glomerular hemodynamics.1 The phenomenon of autoregulatory behavior has been recognized for many decades, but a clear understanding of the underlying mechanisms involved in mediating resistance adjustments remains to be established. As illustrated in Figure 1, pressure-mediated autoregulatory behavior operates by recognizing a change in renal perfusion pressure, or renal vascular transmural pressure, and initiating induction of autoregulatory resistance changes intended to stabilize renal blood flow and/or glomerular filtration rate. The net result is that renal blood flow and glomerular filtration rate remain relatively stable over a wide range of renal perfusion pressures. Autoregulatory behavior is exquisitely sensitive in healthy normal kidneys but significantly less efficient in pathological settings, such as diabetes mellitus and some forms of hypertension. Complete loss of autoregulatory control results in renal blood flow that behaves more passively, thus increasing variability and rendering flow more directly determined by renal perfusion pressure.1,2 Figure 1. Outline of the pressure-induced signaling scheme postulated for autoregulatory adjustments in the afferent arteriolar diameter. Whole kidney autoregulation reflects regulatory input from the myogenic and tubuloglomerular feedback mechanisms at the very least.3–7 Recently, contributions of a third and possibly a fourth mechanism have been suggested.6,7 Consequently, with continued study, the mechanisms underlying renal autoregulatory resistance adjustments are slowly becoming clearer. In addition to the P1 receptor hypothesis put forth to explain signal transduction for tubuloglomerular feedback-dependent resistance changes, we have explored the hypothesis that pressure-mediated autoregulatory responses are mediated by extracellular ATP and activation of P2X1 receptors.3,8,9 Conclusive identification of the signaling molecules that mediate autoregulation remains a point of debate, but it appears clear that the release of a purine-based moiety is required for autoregulatory adjustments in afferent arteriolar resistance.3–5,8–10 This …

Transfer of the CYP4A region of chromosome 5 from Lewis to Dahl S rats attenuates renal injury

This study examined the effect of transfer of overlapping regions of chromosome 5 that includes (4A(+)) or excludes (4A(-)) the cytochrome P-450 4A (CYP4A) genes from the Lewis rat on the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and the development of hypertension-induced renal disease in congenic strains of Dahl salt-sensitive (Dahl S) rats. The production of 20-HETE was higher in the outer medulla of 4A(+) than in Dahl S or 4A(-) rats. Mean arterial pressure (MAP) rose to 190 +/- 7 and 185 +/- 3 mmHg in Dahl S and 4A(-) rats fed a high-salt (HS) diet for 21 days but only to 150 +/- 5 mmHg in the 4A(+) strain. Protein excretion increased to 423 +/- 40 and 481 +/- 37 mg/day in Dahl S and 4A(-) rats vs. 125 +/- 15 mg/day in the 4A(+) strain. Baseline glomerular capillary pressure (Pgc) was lower in 4A(+) rats (38 +/- 1 mmHg) than in Dahl S rats (42 +/- 1 mmHg). Pgc increased to 50 +/- 1 mmHg in Dahl S rats fed a HS diet, whereas it remained unaltered in 4A(+) rats (39 +/- 1 mmHg). Baseline glomerular permeability to albumin (P(alb)) was lower in 4A(+) rats (0.19 +/- 0.05) than in Dahl S or 4A(-) rats (0.39 +/- 0.02). P(alb) rose to approximately 0.61 +/- 0.03 in 4A(-) and Dahl S rats fed a HS diet for 7 days, but it remained unaltered in the 4A(+) rats. The expression of transforming growth factor-beta2 was higher in glomeruli of Dahl S rats than in 4A(+) rats fed either a low-salt (LS) or HS diet. Chronic administration of a 20-HETE synthesis inhibitor (HET0016; 10 mg.kg(-1).day(-1) sc) reversed the fall in MAP and renoprotection seen in 4A(+) rats. These results indicate that the introgression of the CYP4A genes from Lewis rats into the Dahl S rats increases the renal formation of 20-HETE and attenuates the development of hypertension and renal disease.

Molecular mechanisms of proteinuria in diabetes

The epidemic of Type 2 diabetes, and the parallel rising incidence of end-stage renal disease, is progressively increasing worldwide. Kidney disease is one of the major chronic microvascular complications of diabetes, and both metabolic and haemodynamic perturbations participate in its development and progression towards end-stage renal disease. Hypertension and poor metabolic control seem to interact in causing the relentless decline in renal function seen in diabetic patients. Both high circulating glucose levels and increased glomerular capillary pressure act in conjunction in stimulating the different cellular pathways leading to kidney disease. It has been suggested that mechanical forces at the glomerular level may aggravate the metabolic insult by stimulating excessive cellular glucose uptake by up-regulating the facilitative GLUT-1 (glucose transporter-1). We propose the existence of a self-maintaining cellular mechanism whereby a haemodynamic stimulus on glomerular cells induces the up-regulation of GLUT-1, an event followed by greater glucose uptake and activation of intracellular metabolic pathways, resulting in excess TGF-beta1 (transforming growth factor-beta1) production. TGF-beta1, one of the major prosclerotic cytokines in diabetic kidney disease, maintains the up-regulation of GLUT-1, perpetuating a series of cellular events that result, as their ultimate effect, in increased extracellular matrix synthesis and altered permeability of the glomerular filtration barrier. Mechanical and metabolic coupling could represent an important mechanism of injury in the diabetic kidney.

PGE 2 induces COX-2 expression in podocytes via the EP 4 receptor through a PKA-independent mechanism

Cyclooxygenase-2 (COX-2)-dependent prostaglandin E 2 (PGE 2) synthesis correlates with the onset of proteinuria and increased glomerular capillary pressure ( P gc) glomerular disease models. We previously showed that an in vitro surrogate for P gc (cyclical mechanical stretch) upregulates the expression of both COX-2 and the PGE 2 responsive E-Prostanoid receptor, EP 4 in cultured mouse podocytes. In the present study we further delineate the signaling pathways regulating podocyte COX-2 induction. Time course experiments carried out in conditionally-immortalized mouse podocytes revealed that PGE 2 transiently increased phosphorylated p38 MAPK levels at 10 min, and induced COX-2 protein expression at 4 h. siRNA-mediated knockdown of EP 4 receptor expression, unlike treatment with the EP 1 receptor antagonist SC 19220, completely abrogated PGE 2-induced p38 phosphorylation and COX-2 upregulation suggesting the involvement of the EP 4 receptor subtype. PGE 2-induced COX-2 induction was abrogated by inhibition of either p38 MAPK or AMP activated protein kinase (AMPK), and was mimicked by AICAR, a selective AMPK activator, and by the cAMP-elevating agents, forskolin (FSK) and IBMX. Surprisingly, neither PGE 2 nor FSK/IBMX-dependent p38 activation and COX-2 expression were blocked by PKA inhibitors or mimicked by 8-cPT-cAMP a selective EPAC activator, but were instead abrogated by Compound C, suggesting the involvement of AMPK. These results indicate that in addition to mechanical stretch, PGE 2 initiates a positive feedback loop in podocytes that drives p38 MAPK activity and COX-2 expression through a cAMP/AMPK-dependent, but PKA-independent signaling cascade. This PGE 2-induced signaling network activated by increased P gc could be detrimental to podocyte health and glomerular filtration barrier integrity.

The molecular and functional phenotype of glomerular podocytes reveals key features of contractile smooth muscle cells

The glomerular podocyte is a highly specialized cell, with the ability to ultrafilter blood and support glomerular capillary pressures. However, little is known about either the genetic programs leading to this functionality or the final phenotype. We approached this question utilizing a human conditionally immortalized cell line, which differentiates from a proliferating epithelial phenotype to a differentiated form. We profiled gene expression during several time points during differentiation and grouped the regulated genes into major functional categories. A novel category of genes that was upregulated during differentiation was of smooth muscle-related molecules. We further examined the smooth muscle phenotype and showed that podocytes consistently express the differentiated smooth muscle markers smoothelin and calponin and the specific transcription factor myocardin, both in vitro and in vivo. The contractile contribution of the podocyte to the glomerular capillary is controversial. We demonstrated using two novel techniques that podocytes contract vigorously in vitro when differentiated and in real time were able to demonstrate that angiotensin II treatment decreases monolayer resistance, morphologically correlating with enhanced contractility. We conclude that the mature podocyte in vitro possesses functional apparatus of contractile smooth muscle cells, with potential implications for its in vivo ability to regulate glomerular dynamic and permeability characteristics.

Kidney and Circadian Blood Pressure Rhythm

Association between nondipper pattern of circadian rhythm of blood pressure (BP) and impaired renal capacity to excrete sodium into urine was confirmed by Bankir et al1 in this issue of Hypertension based on a large number of subjects. Although this association has been observed in small studies,2,3 their study1 is the first to show it in a large-scale setting, and, therefore, is highly welcomed. Because there is a tight link between kidney and hypertension, renal dysfunction causes hypertension, whereas hypertension accelerates renal damage. It is well appreciated that the kidneys play an important role in the long-term regulation of BP. Usually it takes almost 1 week for kidneys to achieve a new steady-state balance of sodium, when sodium intake is altered. Therefore, renal participation in the short-term BP regulation, such as circadian rhythm, has been overlooked. However, the findings of Bankir et al1 strongly suggest that nocturnal hypertension and nondipper pattern of circadian BP rhythm are because of impaired renal capacity to excrete sodium, and circadian BP rhythm is at least in part regulated by kidneys. Sodium sensitivity of BP is also determined by renal capacity to excrete sodium and is regulated by glomerulotubular balance between glomerular ultrafiltration capability and rate of tubular sodium reabsorption.4 Thus, sodium sensitivity is increased in chronic kidney disease (CKD) where glomerular filtration rate (GFR) is reduced and also in disorders with enhanced tubular sodium reabsorption, including primary aldosteronism, diabetes mellitus, and metabolic syndrome, where GFR is augmented. When sodium sensitivity is increased, glomerular capillary pressure is usually elevated, resulting in albuminuria and renal damage. It becomes evident that, in patients with high-sodium sensitivity, the nocturnal dip in …

Inward rectifier K(+) currents and Kir2.1 expression in renal afferent and efferent arterioles.

The afferent and efferent arterioles regulate the inflow and outflow resistance of the glomerulus, acting in concert to control the glomerular capillary pressure and glomerular filtration rate. The myocytes of these two vessels are remarkably different, especially regarding electromechanical coupling. This study investigated the expression and function of inward rectifier K(+) channels in these two vessels using perfused hydronephrotic rat kidneys and arterioles and myocytes isolated from normal rat kidneys. In afferent arterioles pre-constricted with angiotensin II, elevating [K(+)](0) from 5 to 15 mmol/L induced hyperpolarization (-27 +/- 2 to 41 +/- 3 mV) and vasodilation (6.6 +/- 0.9 to 13.1 +/- 0.6 microm). This manipulation also attenuated angiotensin II-induced Ca(2+) signaling, an effect blocked by 100 micromol/LBa(2+). By contrast, elevating [K(+)](o) did not alter angiotensin II-induced Ca2(+) signaling or vasoconstriction in efferent arterioles, even though a significant hyperpolarization was observed (from -30 +/- 1 to 37 +/- 3 mV, P = 0.003). Both vessels expressed mRNA for Kir2.1 and exhibited anti-Kir2.1 antibody labeling.Patch-clamp measurements revealed prominent inwardly rectifying and Ba(2+)-sensitive currents in afferent and efferent arteriolar myocytes. Our findings indicate that both arterioles express an inward rectifier K(+) current, but that modulation of this current alters responsiveness of only the a different arteriole. The expression of Kir in the efferent arteriole, a resistance vessel whose tone is not affected by membrane potential, is intriguing and may suggest a novel function of this channel in the renal microcirculation.

Preglomerular and postglomerular basal diameter changes and reactivity to angiotensin II in obese rats

Obesity in humans is associated with proteinuria and an increased glomerular filtration, possibly related to an increase in glomerular capillary pressure. We investigated in obese and lean Zucker rats (10-12 weeks old) whether this might be related to alterations in the diameter of preglomerular and postglomerular microvessels and their reactivity to the resistance regulator angiotensin II (AngII), using the hydronephrotic kidney model. The obese rats exhibited a hyperinsulinaemic, euglycaemic state and hypertension. Urinary protein concentration and fluid intake were both increased threefold. Basal diameters of distal interlobular arteries (ILAs) and afferent arterioles (AAs) were larger in the obese rat than in the lean rat (ILA: 25.7 +/- 0.3 vs. 23.0 +/- 0.4 microm and AA: 18.8 +/- 0.3 vs. 16.7 +/- 0.5 microm, respectively; p </= 0.01), while diameters of efferent arterioles (EAs) were smaller in obese animals (14.2 +/- 1.1 vs. 18.2 +/- 1.2 microm; p </= 0.05). AngII induced a concentration-dependent constriction in ILA, AA and EA with an augmented response in the obese compared with the lean rats. Thus, at higher concentrations, AngII abolished the diameter difference between obese and lean animals in preglomerular microvessels while exaggerating that in postglomerular arterioles. Our data indicate that in obese rats, a vasodilated state in small preglomerular microvessels and a vasoconstricted state in the postglomerular arterioles exist. Although AngII cancelled the former, the latter remained. Therefore, these data reveal periglomerular vascular changes that may play a role in glomerular dysfunction and renal pathology associated with obesity.

Can rodent models of diabetic kidney disease clarify the significance of early hyperfiltration?: recognizing clinical and experimental uncertainties

In the past, hyperfiltration and increased glomerular capillary pressure have been identified as important determinants of the development of DN (diabetic nephropathy). Recently, some basic research and clinical reviews on DN have omitted identifying hyperfiltration as an important risk factor. At the same time, different rodent models of DN have been described without and with documented hyperfiltration. In the present review, the importance of hyperfiltration is reassessed, reviewing key clinical and research studies, including the first single nephron studies in a mouse model of DN. From clinical studies of Type 1 and Type 2 diabetes mellitus, it is clear that many patients do not have early hyperfiltration and, even when present, its contribution to subsequent DN remains uncertain. Key mechanisms underlying hyperfiltration in rodent models are reviewed. Findings on intrarenal NO metabolism and the control of single-nephron GFR (glomerular filtration rate) in rodent models of DN are also presented. Characterization of valid experimental models of DN should include a careful delineation of the absence or presence of early hyperfiltration, with special efforts made to establish the specific role hyperfiltration may play in the emergence of DN.