Control Of Renal Blood Flow Research Articles

Macula densa mTORC1 is an important regulator of cellular and aging-dependent kidney functions

Macula densa (MD) cells are major regulators of nephron, kidney, and whole body functions, including the control of renal blood flow, glomerular filtration rate (GFR), renin release and thus the maintenance of body fluid and electrolyte balance. Our recent studies identified the high rate of MD protein synthesis regulated by the mTORC1 complex of the mechanistic target of rapamycin (mTOR) as a novel component of MD cell and glomerular hemodynamic regulatory functions. Raptor is an essential player in mTORC1’s key roles to regulate cell energy homeostasis, growth, protein synthesis, mitochondrial function, apoptosis, and autophagy via phosphorylation of substrates including ribosomal protein S6 kinase (S6K) and eukaryotic translation-initiation factor 4E-binding proteins (4E-BPs). mTORC1 signaling controls the aging process, and deficient mTORC1 activity extends health and lifespan. Therefore, we hypothesized that MD cell-specific mTOR loss of function (lof) prevents aging-related kidney function decline. The present study aimed to demonstrate the key importance of MD cell mTOR activity in renal physiology and aging by characterizing the phenotype of a newly generated genetic MD-mTOR lof mouse model. MD-mTOR lof mice were generated by crossing Nos1-CreERT2 and Raptor floxed mice. Tamoxifen induction (at 3 weeks of age) of Nos1-CreERT2+/- Raptor−/− mice resulted in conditional and inducible Raptor deletion in cells of the Nos1 lineage, which in the kidney is entirely specific to MD cells. Kidney structure/function phenotyping was performed using intravital multiphoton microscopy (MPM), the Medibeacon transdermal GFR measurement system, and tissue harvest, immunohistochemistry, and the OPP incorporation assay of protein synthesis. High and MD-specific Raptor, pS6K, and p4EBP1 immunofluorescence labeling was observed in WT kidney sections. The immunolabeling of these mTOR component and targets were absent specifically in MD cells in MD-mTOR lof mouse kidneys, validating the MD cell-specific genetic approach. The intensity of incorporated OPP labeling was highest in MD cells among all renal cell types in WT. In contrast, MD OPP labeling was significantly reduced in MD-mTOR lof mice indicating diminished, mTORC1-dependent global MD cell protein synthesis. Importantly, in 15-month old aged mice the GFR was significantly higher (preserved) in MD-mTOR lof (1794±197 uL/min/100g BW) compared to WT (1117±61) and MD-mTOR gof (929±61) mice (n=6-18 mice in each group). Altogether, these studies identified mTORC1 as an essential regulator of MD cell biology, and the importance of MD cells in aging-related kidney function decline. MD cells may be important new targets in future anti-aging therapies. DK064234, DK123564, DK135290. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Renal Vascular Resistance Does Not Differ Between Younger Men and Women

PurposeThe incidence of acute kidney injury is nearly two‐fold higher risk in men compared to women. A common cause of acute kidney injury is supply‐demand mismatch that is characterized by the presence of a comparatively low renal oxygen supply (i.e., blood flow) relative to tissue oxygen demand. Thus, it is possible that the control of renal blood flow differs between men and women. For instance, the vasodilator actions of estrogen may protect against excessive renal vasoconstriction or more readily promote renal vasodilation in pre‐menopausal women compared to men. However, whether renal vascular control, a function of both vasoconstrictor and vasodilator capacities, differs between men and women is unknown. Therefore, this study tested the hypotheses that (1) renal vasoconstriction during a sympathetic stimulus (i.e., the cold pressor test, CPT) will be greater in young healthy men compared to young healthy women, and (2) renal vasodilation following an oral protein load will be greater in women compared to men.MethodsHealthy, men (n=13, age 26 ± 3 years) and eumenorrheic women (n=12, age 23 ± 3 years, 4 ± 1 day of menstrual cycle) completed a 2‐min CPT after one hour of supine rest to assess renal vasoconstriction. A whey protein shake (1.2 g of protein/kg of body weight) was ingested 1‐h post‐CPT to assess renal vasodilation. Blood pressure (Penaz method) was measured continually. Renal segmental artery blood velocity (BV, Doppler ultrasound) was measured before and during the CPT (1‐ and 2‐min), and pre‐protein and 75‐ and 150‐min post‐protein. Segmental artery vascular resistance (VR) was calculated as mean arterial pressure (MAP) divided by segmental BV. Data are presented as mean ± SD.ResultsMAP increased in both men and women from pre‐CPT to 2 min (p<0.001), and the magnitude of increase did not differ between men (peak: +25 ± 13 mmHg) and women (peak: +23 ± 9 mmHg, p=0.667). Peak reductions in segmental BV (men: ‐1.3 ± 3.2 cm/s, women: ‐3.7 ± 2.9 cm/s, p=0.065) and increases in segmental VR (men: +1.5 ± 1.0 mmHg/cm/s, women: +2.1 ± 1.0 mmHg/cm/s, p=0.155) during the CPT did not differ between men and women. MAP did not differ between men and women pre‐protein or at 75‐min post‐protein (p>0.586) but was higher in men at 150‐min post‐protein (86 ± 7 mmHg vs. 78 ± 8 mmHg, p=0.042). Peak increases in segmental BV following protein ingestion were greater in women (+5.3 ± 2.2 cm/s) compared to men (+2.7 ± 2.4 cm/s, p=0.009). Similarly, peak reductions in segmental VR were greater in women (‐1.1 ± 0.6 mmHg/cm/s) compared to men (‐0.6 ± 0.6 mmHg/cm/s, p=0.030) following protein ingestion.ConclusionRenal vasoconstrictor responses to sympathetic stimulation do not appear to differ between healthy men and women. However, women displayed greater renal vasodilatory responses to an oral protein load. Therefore, renal vascular control differs between healthy men and women tested in the early follicular phase of the menstrual cycle. These findings may provide mechanistic insights in support of observations that acute kidney injury incidence differs between men and women.

Endothelial KCa 1.1 and KCa 3.1 channels mediate rat intrarenal artery endothelium-derived hyperpolarization response.

Endothelium-derived hyperpolarization (EDH)-mediated response plays an essential role in the control of kidney preglomerular circulation, but the identity of the K+ channels involved in this response is still controversial. We hypothesized that large- (KCa 1.1), intermediate- (KCa 3.1) and small (KCa 2.3) -conductance Ca2+ -activated K+ (KCa ) channels are expressed in the endothelium of the preglomerular circulation and participate in the EDH-mediated response. We study the functional expression of different K+ channels in non-cultured, freshly isolated native endothelial cells (ECs) of rat intrarenal arteries using immunofluorescence and the patch-clamp technique. We correlate this with vasorelaxant responses ex vivo using wire myography. Immunofluorescence revealed the expression of KCa 1.1, KCa 3.1 and KCa 2.3 channels in ECs. Under voltage-clamp conditions, acetylcholine induced a marked increase in the outward currents in these cells, sensitive to the blockade of KCa 1.1, KCa 3.1 and KCa 2.3 channels respectively. Isometric myography experiments, under conditions of endothelial nitric oxide synthase and cyclooxygenase inhibition, showed that blockade either of KCa 1.1 or KCa 3.1 channels was able to reduce the endothelium-derived vasorelaxation of isolated interlobar arteries, while their combined blockade completely abolished it. In contrast, blockade of KCa 2.3 channels did not reduce this vasorelaxant response, despite being functionally expressed in the endothelial cells. This study shows that KCa 1.1 and KCa 3.1 channels are functionally expressed at the renal vascular endothelium and play a central role in the EDH-mediated relaxation of kidney preglomerular arteries, which is important in the control of renal blood flow and glomerular filtration rate.

Purinoceptors, renal microvascular function and hypertension.

Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020).

Extracellular superoxide dismutase is necessary to maintain renal blood flow during sepsis development

BackgroundExtracellular superoxide dismutase (ECSOD) protects nitric oxide (NO) bioavailability by decreasing superoxide levels and preventing peroxynitrite generation, which is important in maintaining renal blood flow and in preventing acute kidney injury. However, the profile of ECSOD expression after sepsis is not fully understood. Therefore, we intended to evaluate the content and gene expression of superoxide dismutase (SOD) isoforms in the renal artery and their relation to renal blood flow.MethodsSepsis was induced in Wistar rats by caecal ligation and perforation. Several times after sepsis induction, renal blood flow (12, 24 and 48 h); the renal arterial content of SOD isoforms, nitrotyrosine, endothelial and inducible nitric oxide synthase (e-NOS and i-NOS), and phosphorylated vasodilator-stimulated phosphoprotein (pVASP); and SOD activity (3, 6 and 12 h) were measured. The influence of a SOD inhibitor was also evaluated.ResultsAn increase in ECSOD content was associated with decreased 3-nitrotyrosine levels. These events were associated with an increase in pVASP content and maintenance of renal blood flow. Moreover, previous treatment with a SOD inhibitor increased nitrotyrosine content and reduced renal blood flow.ConclusionsECSOD appears to have a major role in decreasing peroxynitrite formation in the renal artery during the early stages of sepsis development, and its application can be important in renal blood flow control and maintenance during septic insult.

Eppur Si Muove: The dynamic nature of physiological control of renal blood flow by the renal sympathetic nerves.

Tubuloglomerular feedback and the myogenic response are widely appreciated as important regulators of renal blood flow, but the role of the sympathetic nervous system in physiological renal blood flow control remains controversial. Where classic studies using static measures of renal blood flow failed, dynamic approaches have succeeded in demonstrating sympathetic control of renal blood flow under normal physiological conditions. This review focuses on transfer function analysis of renal pressure-flow, which leverages the physical relationship between blood pressure and flow to assess the underlying vascular control mechanisms. Studies using this approach indicate that the renal nerves are important in the rapid regulation of the renal vasculature. Animals with intact renal innervation show a sympathetic signature in the frequency range associated with sympathetic vasomotion that is eliminated by renal denervation. In conscious rabbits, this sympathetic signature exerts vasoconstrictive, baroreflex control of renal vascular conductance, matching well with the rhythmic, baroreflex-influenced control of renal sympathetic nerve activity and complementing findings from other studies employing dynamic approaches to study renal sympathetic vascular control. In this light, classic studies reporting that nerve stimulation and renal denervation do not affect static measures of renal blood flow provide evidence for the strength of renal autoregulation rather than evidence against physiological renal sympathetic control of renal blood flow. Thus, alongside tubuloglomerular feedback and the myogenic response, renal sympathetic outflow should be considered an important physiological regulator of renal blood flow. Clinically, renal sympathetic vasomotion may be important for solving the problems facing the field of therapeutic renal denervation.

Endothelin contributes to blunted renal autoregulation observed with a high-salt diet.

Autoregulation of renal blood flow (RBF) is an essential function of the renal microcirculation that has been previously shown to be blunted by excessive dietary salt. Endogenous endothelin 1 (ET-1) is increased following a high-salt (HS) diet and contributes to the control of RBF but the differential effects of ET-1 on renal microvessel autoregulation in response to HS remain to be established. We hypothesized that a HS diet increases endothelin receptor activation in normal Sprague-Dawley rats and blunts autoregulation of RBF. The role of ET-1 in the blunted autoregulation produced by a HS diet was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. Using highly selective antagonists, we observed that blockade of either ETA or ETB receptors was sufficient to restore normal autoregulatory behavior in afferent arterioles from HS-fed rats. Additionally, normal autoregulatory behavior was restored in vivo in HS-fed rats by simultaneous ETA and ETB receptor blockade, whereas blockade of ETB receptors alone showed significant improvement of normal autoregulation of RBF. Consistent with this observation, autoregulation of RBF in ETB receptor-deficient rats fed HS was similar to both ETB-deficient rats and transgenic control rats on normal-salt diets. These data support the hypothesis that endogenous ET-1, working through ETB and possibly ETA receptors, contributes to the blunted renal autoregulatory behavior in rats fed a HS diet.

Exercise training attenuates chemoreflex-mediated reductions of renal blood flow in heart failure.

In chronic heart failure (CHF), carotid body chemoreceptor (CBC) activity is increased and contributes to increased tonic and hypoxia-evoked elevation in renal sympathetic nerve activity (RSNA). Elevated RSNA and reduced renal perfusion may contribute to development of the cardio-renal syndrome in CHF. Exercise training (EXT) has been shown to abrogate CBC-mediated increases in RSNA in experimental heart failure; however, the effect of EXT on CBC control of renal blood flow (RBF) is undetermined. We hypothesized that CBCs contribute to tonic reductions in RBF in CHF, that stimulation of the CBC with hypoxia would result in exaggerated reductions in RBF, and that these responses would be attenuated with EXT. RBF was measured in CHF-sedentary (SED), CHF-EXT, CHF-carotid body denervation (CBD), and CHF-renal denervation (RDNX) groups. We measured RBF at rest and in response to hypoxia (FiO2 10%). All animals exhibited similar reductions in ejection fraction and fractional shortening as well as increases in ventricular systolic and diastolic volumes. Resting RBF was lower in CHF-SED (29 ± 2 ml/min) than in CHF-EXT animals (46 ± 2 ml/min, P < 0.05) or in CHF-CBD animals (42 ± 6 ml/min, P < 0.05). In CHF-SED, RBF decreased during hypoxia, and this was prevented in CHF-EXT animals. Both CBD and RDNX abolished the RBF response to hypoxia in CHF. Mean arterial pressure increased in response to hypoxia in CHF-SED, but was prevented by EXT, CBD, and RDNX. EXT is effective in attenuating chemoreflex-mediated tonic and hypoxia-evoked reductions in RBF in CHF.

2014 Young Investigator Award of the American Physiological Society Renal Section

2014 Young Investigator Award of the American Physiological Society Renal Section

Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis*

Nitric oxide plays an important role in the control of renal blood flow and renal function. In sepsis, increased levels of inducible nitric oxide synthase produce excessive nitric oxide, which may contribute to the development of acute kidney injury. We, therefore, examined the effects of intrarenal infusion of selective inducible nitric oxide synthase inhibitors in a large animal model of hyperdynamic sepsis in which acute kidney injury occurs in the presence of increased renal blood flow. Prospective crossover randomized controlled interventional studies. University-affiliated research institute. Twelve unilaterally nephrectomized Merino ewes. Infusion of a selective (1400W) and a partially selective inducible nitric oxide synthase inhibitor (aminoguanidine) into the renal artery for 2 hrs after the induction of sepsis, and comparison with a nonselective inhibitor (Nω-nitro-L-arginine methyl ester). In sheep with nonhypotensive hyperdynamic sepsis, creatinine clearance halved (32 to 16 mL/min, ratio [95% confidence interval] 0.51 [0.28-0.92]) despite increased renal blood flow (241 to 343 mL/min, difference [95% confidence interval] 102 [78-126]). Infusion of 1400W did not change renal blood flow, urine output, or creatinine clearance, whereas infusion of Nω-nitro-L-arginine methyl ester and a high dose of aminoguanidine normalized renal blood flow, but did not alter creatinine clearance. In hyperdynamic sepsis, intrarenal infusion of a highly selective inducible nitric oxide synthase inhibitor did not reduce the elevated renal blood flow or improve renal function. In contrast, renal blood flow was reduced by infusion of a nonselective NOS inhibitor or a high dose of a partially selective inducible nitric oxide synthase inhibitor. The renal vasodilatation in septic acute kidney injury may be due to nitric oxide derived from the endothelial and neural isoforms of nitric oxide synthase, but their blockade did not restore renal function.

The impact of intrarenal nitric oxide synthase inhibition on renal blood flow and function in mild and severe hyperdynamic sepsis*

In experimental hyperdynamic sepsis, renal function deteriorates despite renal vasodilatation and increased renal blood flow. Because nitric oxide is increased in sepsis and participates in renal blood flow control, we investigated the effects of intrarenal Nω-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor, in mild and severe sepsis. Prospective crossover and randomized control interventional studies. University-affiliated research institute. Thirty-two merino ewes. Examination of responses to intrarenal infusion of Nω-nitro-L-arginine methyl ester for 8 hrs in unilaterally nephrectomized normal sheep and in sheep administered Escherichia coli. : In normal sheep, Nω-nitro-L-arginine methyl ester decreased renal blood flow (301 ± 30 to 228 ± 26 mL/min) and creatinine clearance (40.0 ± 5.8 to 31.1 ± 2.8 mL/min), whereas plasma creatinine increased, but fractional excretion of sodium was unchanged. In sheep with nonhypotensive hyperdynamic sepsis, plasma creatinine increased and there were decreases in creatinine clearance (34.5 ± 4.6 to 20.1 ± 3.7 mL/min) and fractional excretion of sodium despite increased renal blood flow. Infusion of Nω-nitro-L-arginine methyl ester normalized renal blood flow and increased urine output, but creatinine clearance did not improve and plasma creatinine and fractional excretion of sodium increased. In sheep with severe hypotensive sepsis, creatinine clearance decreased further (31.1 ± 5.4 to 16.0 ± 1.7 mL/min) despite increased renal blood flow. Infusion of Nω-nitro-L-arginine methyl ester restored mean arterial pressure and reduced renal blood flow but did not improve plasma creatinine or creatinine clearance. In hyperdynamic sepsis, with or without hypotension, creatinine clearance decreased despite increasing renal blood flow. Intrarenal Nω-nitro-L-arginine methyl ester infusion reduced renal blood flow but did not improve creatinine clearance. These data indicate that septic acute kidney injury is not the result of decreased renal blood flow nor is it improved by nonspecific nitric oxide synthase inhibition.

急性腎不全を回避し得た急性 HIV 感染症による重度横紋筋融解症の 1 例

Subjects with primary human immunodeficiency virus (HIV) infection often have acute retroviral syndrome. Some develop rhabdomyolysis, which can lead to acute renal failure. A 21-year-old man admitted for consciousness disturbance was initially considered to have aseptic meningitis associated with primary HIV infection. On hospitalization day 3, he developed severe rhabdomyolysis with elevated serum creatine kinase (CK) of 218,100 IU/L with serum creatinine normal at 0.9 mg/dL. Following massive extracellular fluid infusion and urinary alkalinization, serum CK decreased smoothly, without renal failure. Severe rhabdomyolysis was concomitant with systemic inflammatory response syndrome (SIRS) only on admission day. Acute renal failure in those with rhabdomyolysis may be influenced by renal possibly due to SIRS and tubular damage from reactive oxygen species, rather than by tubular obstruction by myoglobin casts, although this depends on the extent of myolysis. Acute renal failure is prevented in those with primary HIV infection developing rhabdomyolysis, based on renal blood flow control, if condition causing SIRS do not become a complication.

Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice

Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB(-/-)] and wild types [ETB(+/+)] were microperfused. ET-1 constricted AA stronger than EA in ETB(-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases.

Effects of chronic sympatho‐inhibition on reflex control of renal blood flow and plasma renin activity in renovascular hypertension

We determined if chronic sympatho-inhibition with rilmenidine has functional significance for the kidney by altering responses of renal blood flow (RBF) and plasma renin activity (PRA) to stress and acute hypotension in rabbits with renovascular hypertension. RBF to each kidney and renal sympathetic nerve activity (RSNA) to the left kidney were measured in rabbits in which a renal artery clip induced hypertension (2K1C) and in sham-operated rabbits. After 2 weeks, a subcutaneous minipump was implanted to deliver rilmenidine (2.5 mg.kg(-1).day(-1)) to 2K1C rabbits for 3 weeks. After 5 weeks of renal artery stenosis, mean arterial pressure (MAP) was 23% higher and PRA 3-fold greater than in sham-operated rabbits. Blood flow and renal vascular conductance in the stenosed kidney were lower (-75% and -80%) compared with sham, and higher in the non-clipped kidney (68% and 39%). Responses of RBF and PRA to hypotension were similar in 2K1C and sham rabbits. Airjet stress evoked a greater increase in MAP in 2K1C rabbits than sham controls. Chronic rilmenidine normalized MAP, reduced RSNA and PRA, and did not reduce RBF in the stenosed kidney. Responses of RBF (clipped and non-clipped kidney), RSNA and PRA to hypotension and airjet were little affected by rilmenidine. Our observations suggest that chronic sympatho-inhibition is an effective antihypertensive therapy in renovascular hypertension. It normalizes MAP and reduces basal PRA without compromising blood flow in the stenosed kidney or altering responses of MAP, haemodynamics and PRA to acute hypotension and stress.

The renal renin-angiotensin system

The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and tubular epithelial cell sodium chloride and water transport mechanisms. Pharmacological inhibition of the actions of the RAS are widely used in the treatment of patients with hypertension, congestive heart failure, left ventricular dysfunction, pulmonary and systemic edema, diabetic nephropathy, cirrhosis of the liver, scleroderma, and migraines. Therefore, a thorough understanding of the influences of the RAS on normal renal physiology is of major importance for first-year medical students.

Modalités de clampage au cours de la néphrectomie partielle : aspects techniques et conséquences fonctionnelles. Revue du sous-comité rein du Comité de cancérologie de l’Association française d’urologie (CCAFU)

Partial nephrectomy requires control of renal blood flow by using renal vessels clamping. Multiple clamping techniques are available. The clamping procedure can be parenchymal or vascular, involving enbloc arterial and veinous clamping or arterial onlone, being continuous or intermittent, associated or not with renal cooling. The purpose of this present review was to analyze technical aspects of clamping methods during partial nephrectomy and their functional consequences in terms of blood loss, surgical margins status and changes in renal function.

Effect of mesenteric vascular congestion on reflex control of renal blood flow

Portal hypertension initiates a splenorenal reflex, whereby increases in splenic afferent nerve activity and renal sympathetic nerve activity cause a decrease in renal blood flow (RBF). We postulated that mesenteric vascular congestion similarly compromises renal function through an intestinal-renal reflex. The portal vein was partially occluded in anesthetized rats, either rostral or caudal to the junction with the splenic vein. Portal venous pressure increased (6.5 +/- 0.1 to 13.2 +/- 0.1 mmHg; n = 78) and mesenteric venous outflow was equally obstructed in both cases. However, only rostral occlusion increased splenic venous pressure. Rostral occlusion caused a fall in RBF (-1.2 +/- 0.2 ml/min; n = 9) that was attenuated by renal denervation (-0.5 +/- 0.1 ml/min; n = 6), splenic denervation (-0.2 +/- 0.1 ml/min; n = 11), celiac ganglionectomy (-0.3 +/- 0.1 ml/min; n = 9), and splenectomy (-0.5 +/- 0.1 ml/min; n = 6). Caudal occlusion induced a significantly smaller fall in RBF (-0.5 +/- 0.1 ml/min; n = 9), which was not influenced by renal denervation (-0.2 +/- 0.2 ml/min; n = 6), splenic denervation (-0.1 +/- 0.1 ml/min; n = 7), celiac ganglionectomy (-0.1 +/- 0.3 ml/min; n = 8), or splenectomy (-0.3 +/- 0.1 ml/min; n = 7). Renal arterial conductance fell only in intact animals subjected to rostral occlusion (-0.007 +/- 0.002 ml.min(-1).mmHg(-1)). This was accompanied by increases in splenic afferent nerve activity (15.0 +/- 3.5 to 32.6 +/- 6.2 spikes/s; n = 7) and renal efferent nerve activity (32.7 +/- 5.2 to 39.3 +/- 6.0 spikes/s; n = 10). In animals subjected to caudal occlusion, there were no such changes in renal arterial conductance or splenic afferent/renal sympathetic nerve activity. We conclude that the portal hypertension-induced fall in RBF is initiated by increased splenic, but not mesenteric, venous pressure, i.e., we did not find evidence for intestinal-renal reflex control of the kidneys.

Mechanoreceptors and central command

static exercise increases mean arterial pressure, heart rate, and ventilation. Central command and the exercise pressor reflex are the two neural mechanisms causing these responses to static exercise. Central command is defined as the parallel activation of the locomotor and autonomic circuits in

Mechanisms for Renal Blood Flow Control Early in Diabetes as Revealed by Chronic Flow Measurement and Transfer Function Analysis

The purpose of this study was to establish the roles of the myogenic response and the TGF mechanism in renal blood flow (RBF) control at the very earliest stages of diabetes. Mean arterial pressure (MAP) and RBF were measured continuously, 18 h/d, in uninephrectomized control and diabetic rats, and transfer function analysis was used to determine the dynamic autoregulatory efficiency of the renal vasculature. During the control period, MAP averaged 91 +/- 0.5 and 89 +/- 0.4 mmHg, and RBF averaged 8.0 +/- 0.1 and 7.8 +/- 0.1 ml/min in the control and diabetic groups, respectively. Induction of diabetes with streptozotocin caused a marked and progressive increase in RBF in the diabetic rats, averaging 10 +/- 6% above control on day 1 of diabetes and 22 +/- 3 and 34 +/- 1% above control by the end of diabetes weeks 1 and 2. MAP increased approximately 9 mmHg during the 2 wk in the diabetic rats, and renal vascular resistance decreased. Transfer function analysis revealed significant increases in gain to positive values over the frequency ranges of both the TGF and myogenic mechanisms, beginning on day 1 of diabetes and continuing through day 14. These very rapid increases in RBF and transfer function gain suggest that autoregulation is impaired at the very onset of hyperglycemia in streptozotocin-induced type 1 diabetes and may play an important role in the increase in RBF and GFR in diabetes. Together with previous reports of decreases in chronically measured cardiac output and hindquarter blood flow, this suggests that there may be differential effects of diabetes on RBF versus nonrenal BF control.

The Effect of High Glucose and TGF-β on the Cellular Injury in Cultured Glomerular Epithelial Cells

- Abstract Background: The glomerulus is a complex physiological structure, as well as selective filtration barrier in the control of renal blood flow and blood pressure. Glomerular epithelial cells may play an important role in development of diabetic nephropathy. Apoptosis of the glomerular epithelial cells are characterized by disappeara nce of a selective filtration barrier. TGF-s is a key factor in the development of diabetic nephropathy because of its effects on the accumulation of extracellular matrix and mesangial cell proliferation. We examined whether the high glucose and TGF-s induce the apoptosis in cultured rat glomerular epithelial cells. Methods: Glomerular epithelial cells were cultured from rat glomeruli and conditioned with different concentration of TGF-s or high-glucose. We measured apoptosis of cultured rat glomerular epithelial cell conditioning with different concentration of TGF-s or high-glucose by using DNA electrophoresis. Results: High glucose (25 mM) induced apoptosis of cultured rat glomerular epithelial cells compared to controls. TGF-s also induced cell death of cultured rat glomerular epithelial cells in dose dependent manner. Conclusion: These results suggest that high glucose and TGF-s-induced cell death of glomerular epithelial cell may play an important role in diabet ic nephropathy and proteinuria. Pathway of apoptosis or cell death by high glucose and TGF-s must be investigated in the glomerular epithelial cells. (J Kor Diabetes Assoc 30:254~263, 2006)