Glomerular Capillary Pressure Research Articles

Physiopathologie de la progression des maladies rénales

Nephron reduction increases the filtration capacity of the remaining nephrons, which is helpful in the short term, but harmful over the long term The increase in glomerular capillary pressure and in hypertrophy of healthy nephrons stimulates the renin-angiotensin system and TGF-beta. Myofibroblastic transdifferentiation follows, with fibrogenesis and glomerulosclerosis. Converting enzyme inhibitors reduce the expression of genes coding for profibrotic molecules. Proteinuria promotes interstitial fibrosis and must be reduced by drugs that block the renin-angiotensin system.

Effects of p38 mitogen-activated protein kinase inhibition on blood pressure, renal hemodynamics, and renal vascular reactivity in normal and diabetic rats

p38 mitogen-activated protein kinase (p38) has been implicated in mediating vascular smooth muscle and mesangial cell contraction in response to several vasoactive factors, including angiotensin II. Early stages of diabetic nephropathy are associated with renal hemodynamic changes that are, at least in part, attributable to the dysbalance of vasoactive factors that control afferent and efferent arteriolar tone resulting in increased glomerular capillary pressure. Vascular and renal p38 have been found to be activated in diabetes. Therefore, p38 may be involved in the control of systemic and renal hemodynamics in diabetes. To address this issue, mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), metabolic parameters, and plasma renin concentrations (PRC) were determined in streptozotocin-diabetic rats (DM), and in age-matched non-diabetic controls (C), administered with the p38 inhibitor SB 239063 (SB, 50 mg/bwt, p.o.) or with vehicle. Furthermore, renal vascular responses to p38 inhibition (SB 202190, 25 microM) before and after stimulation with the endothelium-dependent vasodilator acetylcholine (ACh) were studied in vitro in tertiary branches of the renal artery from separate groups of DM and C rats, using a fixed support and a force transducer in a myograph system. SB treatment was associated with marked reductions in MAP and GFR in both C and DM rats, whereas RPF remained unchanged, as compared with vehicle-treated animals. Observed differences in MAP and renal hemodynamics were not associated with changes in urinary sodium excretion or PRC. Incubation of KCl-contracted renal arteries from both C and DM rats with the p38 inhibitor resulted in progressive and significant vasorelaxation. Also, vessels from control and diabetic rats treated with the p38 inhibitor exhibited enhancement of ACh-induced vasorelaxation. These data indicate the role of p38 in the control of systemic and renal hemodynamics both in normal and in diabetic rats. The observed effects of p38 inhibition could be mediated at least in part by enhancement of endothelium-dependent vasodilation.

Angiotensin-Converting Enzyme Inhibitors in Veterinary Medicine

Angiotensin-converting enzyme (ACE) inhibitors represent one of the most commonly used categories of drugs in canine and feline medicine. ACE inhibitors currently approved for use in veterinary medicine are benazepril, enalapril, imidapril and ramipril. They are all pro-drugs administered by oral route. A physiologically based model taking into account the saturable binding to ACE has been developed for pharmacokinetic analysis. The bioavailability of the active compounds from their respective pro-drug is low. The active metabolites are eliminated by renal, hepatorenal or biliary excretion, according to the drug. The elimination half-life of the free fraction of the active compounds is very short (ranging from approximately 10 min to 2 h). ACE inhibitors are generally well tolerated. Benazepril, enalapril, imidapril and ramipril are approved for dogs with chronic heart failure (CHF). The efficacy of ACE inhibitors has been convincingly demonstrated in dogs with CHF, especially in those with chronic valvular disease. In such clinical settings, ACE inhibitors improve hemodynamics and clinical signs, and increase survival time. In cats with cardiovascular disease, little information is available except for reports of some benefit in cats with hypertrophic cardiomyopathy in two non-controlled investigations. ACE inhibitors have also a mild to moderate hypotensive effect. There is also evidence to recommend ACE inhibitors in dogs and cats with chronic renal failure (CRF). They decrease the glomerular capillary pressure, have antiproteinuric effects, tend to delay the progression of CRF and to limit the extent of renal lesions.

Is it the low-protein diet or simply the salt restriction?

Dietary factors, such as salt and protein intake, may play an important role in the progression of kidney disease. Consequently, dietary manipulations of these constituents are of interest both in experimental models of kidney disease and in clinical trials with patients with chronic kidney disease to assess whether modification of these exposures will result in a stabilization of disease progression.

Assessment of renal autoregulation

The kidney displays highly efficient autoregulation so that under steady-state conditions renal blood flow (RBF) is independent of blood pressure over a wide range of pressure. Autoregulation occurs in the preglomerular microcirculation and is mediated by two, perhaps three, mechanisms. The faster myogenic mechanism and the slower tubuloglomerular feedback contribute both directly and interactively to autoregulation of RBF and of glomerular capillary pressure. Multiple experiments have been used to study autoregulation and can be considered as variants of two basic designs. The first measures RBF after multiple stepwise changes in renal perfusion pressure to assess how a biological condition or experimental maneuver affects the overall pressure-flow relationship. The second uses time-series analysis to better understand the operation of multiple controllers operating in parallel on the same vascular smooth muscle. There are conceptual and experimental limitations to all current experimental designs so that no one design adequately describes autoregulation. In particular, it is clear that the efficiency of autoregulation varies with time and that most current techniques do not adequately address this issue. Also, the time-varying and nonadditive interaction between the myogenic mechanism and tubuloglomerular feedback underscores the difficulty of dissecting their contributions to autoregulation. We consider the modulation of autoregulation by nitric oxide and use it to illustrate the necessity for multiple experimental designs, often applied iteratively.

Renal function during normal pregnancy and preeclampsia

Glomerular filtration rate and renal plasma flow increase by 40 to 65 and 50 to 85%, respectively, during normal pregnancy in women. Studies using the gravid rat as a model have greatly enhanced our understanding of mechanisms underlying these remarkable changes in the renal circulation during gestation. Hyperfiltration is largely due to increased renal plasma flow, the latter attributable to profound reductions in both the renal afferent and efferent arteriolar resistances. The ovarian hormone, relaxin, mediates renal vasodilation during pregnancy. Relaxin increases vascular gelatinase activity, thereby converting big ET to ET(1-32), which leads to renal vasodilation, hyperfiltration and reduced myogenic reactivity of small renal arteries via the endothelial ET(B) receptor and nitric oxide. Serum concentration of uric acid falls during normal pregnancy as a consequence of increased GFR and/or reduced proximal tubular reabsorption. The elevated urinary excretion of protein during pregnancy is secondary to increased GFR, reduced proximal tubular reabsorption, and perhaps alteration in the electrostatic charge of the glomerular filter. Whether the tubular secretion of Tamm-Horsfall protein increases during normal pregnancy is uncertain. In most women with preeclampsia, renal plasma flow and glomerular filtration rate are at most only modestly decreased as a consequence of increased afferent arteriolar resistance and/or reduced ultrafiltration coefficient. Serum uric acid concentrations are increased mainly as a consequence of reduced renal clearance. Reduced GFR leads to decreased filtered load of uric acid, and plasma volume contraction contributes to increased proximal tubular reabsorption coupled to sodium. The increase in urinary protein excretion in preeclampsia occurs secondary to alterations in the size and/or charge selectivity of the glomerular filter, possible increases in glomerular capillary pressure, and compromise of proximal tubular reabsorption. The renal histologic lesion characteristic of preeclampsia is termed "glomerular endotheliosis". Recent evidence suggests that anti-angiogenic factors emanating from the placenta in preeclampsia contribute to glomerular endotheliosis, proteinuria, and hypertension during disease.

Benidipine Attenuates Glomerular Hypertension and Reduces Albuminuria in Patients with Metabolic Syndrome

Recent studies have shown that metabolic syndrome is associated with an increased risk for chronic kidney disease. We recently found that the prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than that in patients with essential hypertension but without metabolic syndrome. We therefore assessed the effects of benidipine, a long-acting calcium channel blocker, on the sodium sensitivity of blood pressure and renal hemodymamics in 5 patients with metabolic syndrome. Glomerular hemodynamics were assessed using pressure-natriuresis curves, which were constructed by plotting the urinary excretion of sodium as a function of the mean arterial pressure, which was calculated as the mean of 48 values based on 24-h monitoring, during the intake of low (3 g NaCl daily) and relatively high (10 g NaCl daily) sodium diets. Under the relatively high sodium diet condition, benidipine significantly lowered systolic and diastolic blood pressure. The pressure-natriuresis curve was steeper after the administration of benidipine. Benidipine lowered glomerular capillary hydraulic pressure (P(GC)) levels (from 54.4+/-7.5 to 47.0+/-7.0 mmHg, p=0.0152) and reduced both the resistance of the afferent arterioles (from 10,338+/-2,618 to 9,026+/-2,627 dyn.s/cm5, p=0.047) and the resistance of the efferent arterioles (from 4,649+/-2,039 to 2,419+/-2,081 dyn.s/cm(5), p=0.003). The urinary albumin excretion rate also decreased after the administration of benidipine. These findings indicated that benidipine may be effective for reducing the risk of developing chronic kidney disease in patients with metabolic syndrome.

Arterial Hypertension and Kidney Circulation

Hypertension may cause renal vascular lesions and glomerular damage, constituting hypertensive nephrosclerosis. This ultimately may lead to end-stage renal failure, mainly in African-American subjects. Such a situation is exceedingly rare in Caucasian patients with non-malignant hypertension. The direct effect of pressure is well evidenced experimentally in the 2 kidneys-one clip Goldblatt model: only in the unclipped kidney which is exposed to high blood pressure, vascular lesions develop in interlobular arteries and afferent arterioles, followed by glomerular sclerosis. The pressureinduced glomerular damage is limited by an autoregulation based on vasoconstriction of the afferent arteriole. The efficiency of this autoregulation is largely under genetic influence. A deficient autoregulation with vasodilated afferent arterioles leads to more early and severe glomerular damage. Conversely, afferent arteriolar vasodilatation, with glomerular hyperfiltration, may precede any increase in blood pressure. This occurs mainly when sodium excretion is limited, due to any congenital functional defect, or a reduced number of nephrons. Hypertension occurs secondarily, and appears as the hemodynamic counterpart necessary to maintain the sodium balance. In this case, the same primary renal abnormality causes both hypertension and glomerulosclerosis. This is believed to be a frequent cause of hypertension-associated glomerulosclerosis. Whatever the sequence of events, reducing blood pressure is the best way to limit kidney damage. Antihypertensive drugs have, however some actions on renal circulation independent of blood pressure. Calcium channel blockers blunt the autoregulation of afferent arterioles. On the contrary, drugs which inhibit the renin angiotensin system reduce glomerular capillary pressure, and have a beneficial effect on the progression of renal failure. Keywords: Arterial hypertension, Renal circulation, Renal function, Antihypertensive agents

Aldosterone Antagonism in Chronic Kidney Disease

Angiotensin-converting enzyme (ACE) inhibitors are potent members of the arsenal to treat chronic kidney disease (CKD). By reducing blood pressure (BP) and disproportionately decreasing intraglomerular pressure, this class of drugs also reduces proteinuria and slows progression of CKD (1,2). Given the high prevalence of cardiovascular disease in this population, it is noteworthy that ACE inhibitors also decrease the incidence of stroke, myocardial infarction (MI), and cardiovascular mortality in patients who are at high cardiovascular risk (3). More recently, data reporting similar benefits of angiotensin receptor blockers (ARB) support their use in the treatment of CKD as well, especially in individuals with type 2 diabetes (4). Furthermore, one sizable study suggested that the combination of an ACE inhibitor and ARB may be more effective than either agent alone (5). Parving and colleagues (6) called attention to the effects of high-dose ARB therapy, up to three times the recommended dose, as an additional means of effectively interrupting the renin-angiotensin-aldosterone system (RAAS). By logical extension, further blockade of the RAAS by direct antagonism of aldosterone also may prove beneficial. Indeed, aldosterone seems to be a potent effector of renal injury (7–9). In the rare cases of primary aldosteronism and its functional analogue, the even more rare Liddle’s syndrome, the observed renal injury probably is independent of the more proximal elements of the RAAS (10,11). Animal models provide an expeditious tool for assessing pathophysiologic change and the efficacy of intervention. The classic model of primary aldosteronism, the mineralocorticoid–nephrectomy–high-salt model of hypertension, develops systemic and glomerular capillary hypertension and sustains renal damage (12). In the remnant kidney model of CKD, ACE inhibitors and ARB attenuate renal injury (13). However, this protection, which is associated with suppression of aldosterone secretion, is abrogated by exogenous aldosterone infusion with return of …

Podocytes are sensitive to fluid shear stress in vitro

Podocytes are exposed to mechanical forces arising from glomerular capillary pressure and filtration. It has been shown that stretch affects podocyte biology in vitro and plays a significant role in the development of glomerulosclerosis in vivo. However, whether podocytes are sensitive to fluid shear stress is completely unknown. In the present study, we therefore exposed cells of a recently generated conditionally immortalized mouse podocyte cell line to defined fluid shear stress in a flow chamber, mimicking flow of the glomerular ultrafiltrate over the surface of podocytes in Bowman's space. Shear stress above 0.25 dyne/cm(2) resulted in dramatic loss of podocytes but not of proximal tubular epithelial cells (LLC-PK(1) cells) after 20 h. At 0.015-0.25 dyne/cm(2), lamellipodia formation in podocytes was enhanced and the actin nucleation protein cortactin was redistributed to the cell margins. Shear stress further diminished stress fibers and the presence of vinculin in focal adhesions. Linear zonula occludens-1 distribution at cell-cell contacts remained unaffected at low shear stress. At 0.25 dyne/cm(2), the monolayer was broken up and remaining cell-cell contacts were reinforced by F-actin and alpha-actinin. Because the cytoskeletal changes induced by shear stress suggested the involvement of tyrosine kinases (TKs), we tested several TK inhibitors that were all without effect on podocyte number under static conditions. At 0.25 dyne/cm(2), however, the TK inhibitors genistein and AG 82 were associated with marked podocyte loss. Our data demonstrate that podocytes are highly sensitive to fluid shear stress. Shear stress induces a reorganization of the actin cytoskeleton and activates specific tyrosine kinases that are required to withstand fluid shear stress.

Diagnosis and Management of Ischemic Nephropathy

Analysis of the Third National Health and Nutrition Examination Survey (1988 to 1994) suggests that chronic kidney disease (CKD) is a major public health problem (1). Approximately 11% of the US population has CKD. Roughly half have a GFR <60 ml/min per 1.73 m2 with or without kidney damage (stages 3 to 4), and half have exclusively kidney damage as manifested by microalbuminuria (stages 1 to 2) (2). It is widely recognized that the prevalence of stage 5 CKD is also increasing at a rapid rate, and it is estimated that the number of patients who have ESRD may reach 2.24 million by 2030 (3). Evidence to establish reduced GFR as an independent risk factor for cardiovascular disease (CVD) mortality has emerged. Analysis of data from several population-based epidemiologic studies (4,5) demonstrates poorer outcomes regarding stroke, myocardial infarction, and congestive heart failure (CHF) in patients with even mild compromise of kidney function. The morbidity of this group of patients constitutes an economic burden both directly in terms of resource utilization and indirectly through loss of productivity and impaired quality of life (2). Atherosclerotic renovascular disease (ARVD) can result in renovascular hypertension. However, ARVD is an increasingly recognized cause of CKD (6,7). In this article, we focus mainly on ARVD or renal artery stenosis (RAS) secondary to atherosclerosis as a cause of ischemic nephropathy. ARVD is a disease of aging, and several studies have shown its strong association with extrarenal atherosclerotic disease (8–10). Patients with ARVD seem to be at a much greater risk for cardiovascular death than for progressing to renal replacement therapy (11). Whether renal revascularization can benefit renal and cardiovascular outcomes has not been established. Atherosclerosis is the cause of approximately 90% of RAS in adults who are older …

Sirolimus-Associated Proteinuria and Renal Dysfunction

Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.

Modulation by NO of renal myogenic autoregulation: TGF dependency

Blood flow to the kidney is unique in that it is regulated to serve the urine-producing function of the kidney and is far in excess of any conceivable metabolic demand. As renal blood flow (RBF) is so high, and resistance thus so low, the capillaries in the glomerulus are potentially exposed to high transmural pressures. The need to stabilize glomerular capillary pressure plus the need for stable tubular loads to permit regulation of salt excretion has focused attention on the mechanisms by which RBF is stabilized when blood pressure fluctuates. Renal autoregulation, i.e. regulation by the kidney of its own blood flow, effectively stabilizes RBF over a wide range of blood pressure. In turn, autoregulation is the product of two mechanisms: a myogenic mechanism located entirely within the vascular smooth muscle of the preglomerular microcirculation, and tubuloglomerular feedback (TGF) by which information about the distal tubular load is transmitted through the macula densa and the juxtaglomerular apparatus to the afferent arteriole. Both these mechanisms are extensively modulated by a variety of paracrine and endocrine agents. In the 15 years since Tolins et al. (1990) showed that the nitro-arginine derivative Nω-monomethyl-l-arginine (l-NMMA) causes profound renal vasoconstriction, a great number of studies have been performed to characterize and understand the contribution of nitric oxide to the regulation of RBF. These studies have revealed that the renal circulation is perhaps the most sensitive in the body to non-selective inhibition of nitric oxide synthase (NOS) with complete inhibition causing at least a twofold increase in renal vascular resistance that is independent of the pronounced pressor response seen after systemic NOS inhibition. Early studies did not detect any effect of NOS inhibition on renal autoregulation. More recent studies using the classic steady-state, pressure ramp approach have shown that the lower pressure limit of autoregulation is extended to still lower pressures. At the same time, time series analysis has shown distinct augmentation of the myogenic mechanism after non-selective NOS inhibition. These effects have largely been attributed to inhibition of endothelial NOS although the kidney also contains neuronal NOS (nNOS), located largely at and around the macula densa. While selective inhibition of nNOS has been problematic, a number of studies have combined to demonstrate that inhibition of nNOS at the macula densa causes a stronger TGF response (e.g. Ichihara et al. 1998 and other references found in Just & Arendshorst, 2005). In this issue of The Journal of Physiology, Just & Arendshorst (2005) report studies that bear on two aspects of how NO affects renal autoregulation. As non-selective NOS inhibition causes such strong renal vasoconstriction, it is often considered that the enhancement of autoregulation is a consequence of the vasoconstriction. However, blood pressure fluctuates both upward and downward and NOS inhibition improves the stabilization of RBF. The major point made by Just and Arendshorst is the demonstration, which was logically necessary, that non-selective NOS inhibition augments both pressure-induced vasoconstriction and pressure-induced vasodilatation in the kidney. This finding is supported by the demonstration that equivalent vasoconstriction caused by Ang II does not duplicate the autoregulatory result, showing that the vasoconstriction is not sufficient to explain the change in autoregulation. In addition, they show in the same rats that non-selective NOS inhibition does not alter myogenic autoregulation in the hindquarters, indicating regional specificity. The authors further show that the augmentation of renal myogenic autoregulation induced by non-selective NOS inhibition is abrogated in the presence of furosemide. Furosemide of course is a loop diuretic which, at the dose used, blocks NaCl reabsorption from the thick ascending limb and effectively clamps TGF off. The strength of this interaction is somewhat surprising, given that both sources of nitric oxide within the renal cortex were inhibited, only one of which is under TGF control, and that nitric oxide is highly diffusive. However, this is undoubtedly a very interesting result that indicates regulation of the myogenic mechanism by tubular elements. Thus, a control system, TGF, that plays an important role linking renal inputs (RBF and GFR) to output (tightly regulated salt excretion) has now been linked mechanistically to the other autoregulatory system that had been presumed to be independent of tubular function.

Aldosterone and the kidney: Rapid regulation of renal microcirculation

Recent studies provide evidence that aldosterone (Aldo) accelerates hypertension, proteinuria and glomerulosclerosis in animal models of chronic renal failure. Although the underlying mechanisms are not well defined, Aldo may exert these deleterious renal effects by elevating renal vascular resistance (RVR) and glomerular capillary pressure (P GC). To test this possibility, we studied the action of Aldo on rabbit afferent (Af-) and efferent arterioles (Ef-Arts), crucial vascular segments to the control of glomerular hemodynamics. Aldo caused rapid (within 5 min) constriction in both arterioles. The constriction was not affected by spironolactone but was reproduced by membrane-impermeable albumin-conjugated Aldo, suggesting that vasoconstrictor actions are non-genomic. This notion was further supported by the finding that neither actinomycin D nor cycloheximide had effect. The vasoconstrictor action of Aldo on Af-Arts was inhibited by nifedipine (L-type calcium channel blocker), whereas that on Ef-Arts was inhibited by efonidipine (both L- and T-type calcium channel blocker) but not nifedipine. Disrupting the endothelium or nitric oxide (NO) synthesis inhibition augmented the vasoconstriction in Af-Arts, demonstrating that endothelium-derived NO modulates the vasoconstrictor actions of Aldo. Thus, Aldo causes non-genomic vasoconstriction via calcium mobilization thorough L- or T-type calcium channels in Af- or Ef-Arts, respectively. These vasoconstrictor actions on the glomerular microcirculation may play an important role in the pathophysiology and progression of renal diseases by elevating RVR and P GC, especially when endothelium functions are impaired. In addition to our study, this review describes recent findings on the rapid cardiovascular actions of Aldo, with a particular attention to the renal hemodynamics.

Pathophysiology of disease progression in proteinuric nephropathies

Many patients with proteinuric chronic nephropathies progress inexorably to end-stage renal failure (ESRF), which is usually associated with the histologic findings of glomerulosclerosis and interstitial fibrosis [1]. In the last two decades clarification of the mechanisms of injury underlying the progression of chronic proteinuric nephropathies has been a major challenge for the renal community. Experimental renal ablation in the rat was instrumental in clarifying the pathophysiology of renal adaptation to nephron loss [2]. After removal of a critical portion of renal mass, remnant intact nephrons undergo sudden hypertrophy with concomitant lowering of arteriolar resistance and increased glomerular plasma flow. Because the tone of afferent arterioles drops more than the efferent ones, glomerular capillary hydraulic pressure rises, and more filtrate is formed per nephron. While such changes serve to enhance the filtration capacity of remaining nephron units, thus minimizing the functional consequences of nephron loss, they are ultimately detrimental. Indeed, the high intraglomerular capillary pressure enlarges the radii of the pores perforating the glomerular capillary barrier by a mechanism at least partly mediated by angiotensin (Ang) II. This impairs the size-selective function of the barrier and causes protein ultrafiltration. An excess of proteins in the lumen of the proximal tubules, and the secondary process of tubular epithelial endocytosis may exert a nephritogenic effect. Analysis of renal biopsy specimens from rats with doxorubicin-induced nephrosis [3] or age-related proteinuria [4] showed the accumulation of filtered proteins in the cytoplasm of proximal tubular cells, associated with interstitial inflammatory reactions and tubulointerstitial fibrotic and glomerulosclerotic lesions. Several other studies in rat models revealed a close link between abnormal permeability of the glomerular capillary barrier to proteins and the subsequent renal structural injury. Examples are streptozotocin-induced diabetes, the

Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney

To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum; P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg; P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.

Nonlinear interactions in renal blood flow regulation

We have developed a model of tubuloglomerular feedback (TGF) and the myogenic mechanism in afferent arterioles to understand how the two mechanisms are coupled. This paper presents the model. The tubular model predicts pressure, flow, and NaCl concentration as functions of time and tubular length in a compliant tubule that reabsorbs NaCl and water; boundary conditions are glomerular filtration rate (GFR), a nonlinear outflow resistance, and initial NaCl concentration. The glomerular model calculates GFR from a change in protein concentration using estimates of capillary hydrostatic pressure, tubular hydrostatic pressure, and plasma flow rate. The arteriolar model predicts fraction of open K channels, intracellular Ca concentration (Ca(i)), potential difference, rate of actin-myosin cross bridge formation, force of contraction, and length of elastic elements, and was solved for two arteriolar segments, identical except for the strength of TGF input, with a third, fixed resistance segment representing prearteriolar vessels. The two arteriolar segments are electrically coupled. The arteriolar, glomerular, and tubular models are linked; TGF modulates arteriolar circumference, which determines vascular resistance and glomerular capillary pressure. The model couples TGF input to voltage-gated Ca channels. It predicts autoregulation of GFR and renal blood flow, matches experimental measures of tubular pressure and macula densa NaCl concentration, and predicts TGF-induced oscillations and a faster smaller vasomotor oscillation. There are nonlinear interactions between TGF and the myogenic mechanism, which include the modulation of the frequency and amplitude of the myogenic oscillation by TGF. The prediction of modulation is confirmed in a companion study (28).

TGF-beta impairs renal autoregulation via generation of ROS.

Impaired autoregulation in chronic kidney disease can result in elevation of glomerular capillary pressure and progressive glomerular damage; however, the factors linking chronic glomerular disorders to impaired autoregulation have not been identified. We tested the hypothesis that the cytokine most closely associated with progressive glomerular disease, transforming growth factor (TGF)-beta, may also attenuate autoregulation. Kidneys from normal rats were prepared for videomicroscopy, using the blood-perfused juxtamedullary nephron technique. Autoregulatory responses were measured under control conditions and during superfusion with TGF-beta1 (10 ng/ml). Control afferent arteriolar diameter averaged 18.4 +/- 1 microm and significantly decreased to 16.3 +/- 0.9 and 13.2 +/- 0.8 microm at perfusion pressures of 130 and 160 mmHg, respectively. In the presence of TGF-beta1, autoregulatory responses were completely blocked. In similar experiments performed using PDGF-BB (10 ng/ml) and HGF (25 ng/ml), the normal autoregulatory response was not affected. In vitro studies, using isolated preglomerular vascular smooth muscle cells, revealed that exposure to TGF-beta1 stimulated a rapid increase in reactive oxygen species (ROS) that was inhibited by NADPH oxidase inhibitors. In situ studies, with dihydroethidium staining, revealed a marked increase in renal vessel ROS production on exposure to TGF-beta1. Pretreatment of the juxtamedullary afferent arterioles with tempol, a ROS scavenger, or with apocynin, a NADPH oxidase inhibitor, prevented the impaired autoregulation induced by TGF-beta1. These data reveal a novel hemodynamic pathway by which TGF-beta could lead to progressive glomerular injury by impairing normal renal microvascular function.

Effects of isoprostane on tubuloglomerular feedback: roles of TP receptors, NOS, and salt intake

A thromboxane prostanoid receptor (TP-R) agonist U-46,619 enhances tubuloglomerular feedback (TGF). Glomerular expression of TP-R and enhancement of TGF by U-46,619 increase with salt intake. We investigated the hypothesis that 8-isoprostaglandin F(2alpha) (8-Iso) activates TGF via TP-R. The maximal TGF response in rats was assessed from the fall in proximal stop flow pressure (PSF; an index of glomerular capillary pressure) during loop of Henle (LH) microperfusion of artificial tubular fluid (ATF) at 40 nl/min. Microperfusion of 8-Iso (10(-4) M) into the efferent arteriole (EA) enhanced TGF responses by 20 +/- 3% (P < 0.01). TGF response to 8-Iso was independent of dietary salt [DeltaTGF%, low salt (LS): 21 +/- 5%; normal salt (NS): 17 +/- 4%; high salt (HS): 29 +/- 8%, not significant (ns)], unlike the salt-dependent effect of U-46,619 (DeltaTGF%, LS: 41 +/- 5%; NS: 52 +/- 4%; HS: 112 +/- 21%). Ifetroban, the TP-R antagonist, abolished TGF responses to 8-Iso and U-46,619 at all levels of salt intake. During luminal perfusion of N-monomethyl-l-arginine (l-NMA), the effect of 8-Iso on TGF was enhanced in NS and HS but not in LS (LS: 22 +/- 6 vs. LS + l-NMA: 28 +/- 6%, ns; NS: 18 +/- 4 vs. NS + l-NMA: 40 +/- 4, P < 0.01; HS: 27 +/- 3 vs. HS + l-NMA: 65 +/- 6, P < 0.01). However, U-46,619 did not further increase TGF after l-NMA in all salt groups (LS: 43 +/- 7 vs. LS + l-NMA: 51 +/- 6, ns; NS: 52 +/- 7 vs. NS + l-NMA: 48 +/- 8, ns; HS: 114 +/- 21 vs. HS + l-NMA: 74 +/- 22, ns). In conclusion, activation of TP receptors by U-46,619 and 8-Iso-PGF(2alpha) enhances TGF. In addition, the effect of U-46,619 was salt dependent, whereas the effect of 8-Iso-PGF(2alpha) was salt independent. However, stimulation of NO by 8-isoprostanes masks its salt-sensitive effect on TGF.

Human Podocytes Possess a Stretch-Sensitive, Ca2+-Activated K+ Channel

Podocytes express many proteins characteristic of smooth muscle, such as actin and myosin. They also express receptors to several vasoactive agents, including acetylcholine and angiotensin II; these phenotypic properties suggest that podocytes are not static entities but may respond to physiologic stimuli. The electrophysiologic properties of a conditionally immortalized human podocyte cell line that expresses the specific podocyte proteins nephrin, podocin, and synaptopodin were examined by patch clamp. Channels that were highly K(+)-selective and had a conductance of 224 +/- 11.5 pS in symmetrical 150 mM K(+) solutions were identified. Channel activity was Ca(2+)- and voltage-dependent, being increased with an increase in Ca(2+) or depolarization, and inhibited by penitrem A. The conductance and voltage- and Ca(2+)-dependence suggest that this is the large-conductance calcium-activated K(+) channel, BK (KCNMA1)-this was supported by reverse transcription-PCR experiments that showed the presence of the BK encoding mRNA, along with expression of KCNMB subunit types 3 and 4. In sections of human glomeruli, immunocytochemistry revealed that BK co-localizes with the podocyte-specific protein nephrin, indicating that these channels are present in native human podocytes. In whole-cell experiments, penitrem A inhibited outward currents to the same extent as tetra-ethyl ammonium (TEA) but did not affect the membrane potential. Channel activity was also increased by applying suction to the patch pipette or by dilution of the bathing medium, indicating that these channels are stretch sensitive. Thus, these channels do not contribute to the resting membrane potential but are activated by a rise in intracellular Ca(2+), membrane depolarization, cell swelling, or membrane stretch. By implication, these results suggest that podocytes may be able to respond to changes in the glomerular capillary pressure and modulate the GFR.