Roland Blantz - Academia.edu (original) (raw)

Papers by Roland Blantz

Research paper thumbnail of Glomerular hemodynamics in cell-free and erythrocyte-perfused isolated rat kidney

The American journal of physiology

The cell-free isolated perfused kidney (IPK) is characterized by normal glomerular filtration rat... more The cell-free isolated perfused kidney (IPK) is characterized by normal glomerular filtration rate (GFR) and very low filtration fraction (FF). Addition of erythrocytes to the perfusate (IEPK) increases FF while maintaining "normal" GFR levels. Micropuncture studies were performed in IPK and IEPK to establish the determinants of the glomerular ultrafiltration process responsible for low FF in IPK and to evaluate the impact of the addition of erythrocytes on these determinants. Nephron filtration rate was similar in IPK and IEPK (40 +/- 4 vs. 39 +/- 4 nl/min), whereas nephron perfusate flow was significantly higher in IPK (1,247 +/- 100 vs. 112 +/- 13 nl/min), leading to a superficial nephron FF of 3.4 +/- 0.2% in IPK and 36 +/- 2% in IEPK. Glomerular hydrostatic pressure (PG) and transcapillary hydrostatic pressure gradient (delta P) were 53 +/- 2 and 33 +/- 1 mmHg, respectively, in IPK and 51 +/- 3 and 34 +/- 2 mmHg in IEPK, all normal values. Glomerular arteriolar resistances were significantly lower in IPK than in IEPK, and the glomerular ultrafiltration coefficient (LpA) was significantly lower in IPK (0.053 +/- 0.010 vs. 0.100 +/- 0.020 nl.s-1.mmHg-1), but both values are within the normal in vivo range. These results demonstrate that low FF in IPK is not due to decreased delta P or LpA values but to the high renal perfusion rate required to maintain normal PG and delta P values. Addition of erythrocytes increases glomerular arteriolar resistances and restores glomerular hemodynamics to a pattern nearly identical to in vivo conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: Effect of sodium and salt restriction

Journal of the American Society of Nephrology

Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats,... more Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats, the effect of a low-sodium (LNa) and a low-salt (LNaCl) diet on renal function and on plasma and kidney tissue angiotensin II (AIIp, AIIk) was tested. Clearance experiments were performed in anesthetized rats 7 days after starting on LNa or LNaCl. On a control diet, STZ exhibited an increase in GFR, RBF, and kidney weight (KW) and a reduction in renal vascular resistance (RVR) and AIIk, but no change in AIIp, compared with nondiabetic normal rats (CON). Although sodium restriction reduced and salt restriction increased AIIk in CON, both diets increased AIIp without affecting renal hemodynamics or KW. In diabetic rats, both salt and sodium restriction further increased GFR and RBF by reducing RVR, increased KW, and changed AIIk and AIIp in a similar pattern, but at significantly lower values compared with CON. Daily treatment of STZ-LNa with the AII-receptor blocker losartan (20 mg/L, in drinking water) did not affect the reduction in RVR and the increase in KW but slightly reduced RBF because of a decrease in mean arterial blood pressure and further increased GFR. It was concluded that (1) AIIk but not AIIp is affected differently by LNa compared with LNaCl in both CON and STZ; (2) LNaCl and LNa change AIIp and AIIk in a similar pattern but at significant lower values in STZ compared with CON; and (3) with regard to renal hemodynamics and KW, the response to LNa and LNaCl is different in CON compared with rats 6 wk after the onset of diabetes mellitus, the latter exhibiting a further increase in renal hyperfiltration and KW by a mechanism that is not directly AII receptor dependent.

Research paper thumbnail of Glomerular and tubular interactions between renal adrenergic activity and nitric oxide

The American journal of physiology

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtrat... more Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5-9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3',5'-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.

Research paper thumbnail of Role of angiotensin in the regulation of renal response to proteins

Seminars in Nephrology

Intrarenal and extrarenal humoral factors have been proposed as mediators and modulators of the r... more Intrarenal and extrarenal humoral factors have been proposed as mediators and modulators of the renal hyperemic response to amino acid infusion. Among the potential modulators, angiotensin II (AII) constitutes the most important candidate due to its critical role in the control of glomerular and tubular function. The modulatory effect of AII has been assessed by (1) measuring the changes in plasma renin activity (PRA)/AII during the normal hyperemic response, and (2) by assessing the levels of PRA/AII and the response to AII-suppressing agents in conditions with no vasodilatory response during amino acid infusion. Administration of a protein load in normal animals or humans does not modify PRA/AII. Absence of a vasodilatory response in various experimental conditions (nitric oxide blockade in normal rats, experimental models of hypertension, diabetes mellitus, chronic glomerulonephritis, cyclosporine administration) is characterized by a significant decrease in proximal tubular reabsorption during amino acid infusion. Converting enzyme inhibitors or AII receptor antagonist restore normal tubular function and the increase in glomerular filtration rate during amino acid infusion. Absence of a vasodilatory response is also associated with increases in kidney AII levels in some of these conditions. These results suggest that (1) AII modulates the amino acid-induced hyperemia through its inhibitory effect on proximal tubular reabsorption and activation of the tubuloglomerular feedback system, and (2) that the expression of the modulatory effect of AII may depend on the interaction between AII and other intrarenal systems like nitric oxide.

Research paper thumbnail of Role of nitric oxide in glomerular physiology and pathophysiology

Advances in nephrology from the Necker Hospital

Research paper thumbnail of Role of nitric oxide in renal hemodynamics

Seminars in Nephrology

Studies performed over the last 10 years have evaluated the role of nitric oxide (NO) in the cont... more Studies performed over the last 10 years have evaluated the role of nitric oxide (NO) in the control of renal hemodynamics. This article reviews the effects of administration of nitric oxide synthase (NOS) blockers on renal function in experimental animals and human volunteers. These studies show that NOS blockade increases renal vascular resistances and decreases the glomerular ultrafiltration coefficient. These experimental studies also support the presence of an important interaction between NO, angiotensin II, and renal nerves in the control of renal function. The use of acute and chronic administration of NOS blockers has generated a great deal of new and exciting information regarding the role of NO in the regulation of normal renal function.

Research paper thumbnail of Physiology of the Renal Circulation

Ascites and Renal Dysfunction in Liver Disease, 2005

Research paper thumbnail of Temporal adjustment of the juxtaglomerular apparatus during sustained inhibition of proximal reabsorption

Journal of Clinical Investigation, 1999

Tubuloglomerular feedback (TGF) stabilizes nephron function by causing changes in single-nephron ... more Tubuloglomerular feedback (TGF) stabilizes nephron function by causing changes in single-nephron GFR (SNGFR) to compensate for changes in late proximal flow (VLP). TGF responds within seconds and reacts over a narrow range of VLP that surrounds normal VLP. To accommodate sustained increases in VLP, TGF must reset around the new flow. We studied TGF resetting by inhibiting proximal reabsorption with benzolamide (BNZ; administered repeatedly over a 24-hour period) in Wistar-Froemter rats. BNZ acutely activates TGF, thereby reducing SNGFR. Micropuncture was performed 6-10 hours after the fourth BNZ dose, when diuresis had subsided. BNZ caused glomerular hyperfiltration, which was prevented with inhibitors of macula densa nitric oxide synthase (NOS). Because of hyperfiltration, BNZ increased VLP and distal flow, but did not affect the basal TGF stimulus (early distal salt concentration). BNZ slightly blunted normalized maximum TGF response and the basal state of TGF activation. BNZ sensitized SNGFR to reduction by S-methyl-thiocitrulline (SMTC) and caused the maximum TGF response to be strengthened by SMTC. Sensitization to type I NOS (NOS-I) blockers correlated with increased macula densa NOS-I immunoreactivity. Tubular transport measurements confirmed that BNZ affected TGF within the juxtaglomerular apparatus. During reduced proximal reabsorption, TGF resets to accommodate increased flow and SNGFR through a mechanism involving macula densa NOS.

Research paper thumbnail of The Renal Response to Sepsis and the Role of NOS Isoforms

The clinical syndrome of sepsis is characterized by the conjunction of systemic hypotension and m... more The clinical syndrome of sepsis is characterized by the conjunction of systemic hypotension and multiorgan failure leading to high morbidity and mortality . The reduction in systemic blood pressure is primarily the result of generation of excess nitric oxide by cytokine dependent transcription of inducible nitric oxide synthase . However, the failure of various organs, particularly renal dysfunction, is not merely the consequence of systemic hypotension, but rather results from vasoconstriction resulting in a marked reduction in glomerular~ltration rate . The question, therefore, arises "Why, if systemic hypotension is the result of generation of the vasodilator, NO, does renal vasoconstriction and renal failure occur?" There must be speci~c mechanisms which exclude the kidney, and potentially other organs, from sharing in the more generalized reduction in vascular resistance. Renal failure considerably complicates the treatment of the sepsis syndrome and therefore this apparent pathophysiologic enigma requires further investigation.

Research paper thumbnail of An analysis of renal nitric oxide contribution to hyperfiltration in diabetic rats

Journal of Laboratory and Clinical Medicine, 2001

Research paper thumbnail of Adenosine A<sub>1</sub> Receptors Determine Glomerular Hyperfiltration and the Salt Paradox in Early Streptozotocin Diabetes Mellitus

Research paper thumbnail of Glycine Prevents Toxic Tubular Cell Injury

Renal Failure, 1994

Glycine prevents tubular injury as suggested by in vitro cell culture studies, studies in the iso... more Glycine prevents tubular injury as suggested by in vitro cell culture studies, studies in the isolated perfused kidney, and in vivo studies. We have previously demonstrated that intratubular administration of uranyl nitrate (UN) produces proximal tubular cell injury and decreases proximal tubular reabsorption (APR). The decrease in APR activates tubuloglomerular feedback and lowers nephron filtration rate (SNGFR). This study was designed to evaluate if glycine administration could prevent the decrease in SNGFR after UN administration and if maintenance of SNGFR was due to tubular cell cytoprotection or suppression of the tubuloglomerular feedback. Administration of 0.65 ng of UN into the early proximal tubule was associated with a decrease in distal SNGFR (SNGFRD) from 29 +/- 2 to 24 +/- 2 nL/min (p &lt; .05) and late proximal SNGFR (SNGFRLP) from 37 +/- 2 to 26 +/- 2 nL/min, and APR from 14 +/- 1 to 10 +/- 1 nL/min. Systemic administration of glycine (20 g/dL, 1.4 mL/h) was associated with significant increases in SNGFRD and SNGFRLP, and APR (38 +/- 3, 44 +/- 3, and 15 +/- 2 nL/min). UN administration did not affect APR or SNGFR in glycine-treated rats. These findings demonstrate that glycine prevents UN-induced decreases in SNGFR through a cytoprotective effect on proximal tubular cells.

Research paper thumbnail of Vascular contributions to pathogenesis of acute renal failure

Renal Failure, 1998

ABSTRACT

Research paper thumbnail of Renal functional reserve in treated and untreated hypertensive rats

Kidney International, 1991

Renal functional reserve (renal response to protein loading, RFR) has been suggested as a method ... more Renal functional reserve (renal response to protein loading, RFR) has been suggested as a method to verify the presence of hyperfiltration. This study was designed to evaluate the role of RFR as an indicator of increased glomerular capillary hydrostatic pressure in short-term treated and untreated rats with two-kidney, one-clip Goldblatt hypertension. One month after placing a silver clip, micropuncture studies were performed on the unclipped kidney. Normal rats and three groups of clipped rats [untreated group (HYP), a group treated with captopril (CEI) and a group treated with verapamil (VER) 5 days before the micropuncture studies] were studied. Glomerular hemodynamics and proximal tubular reabsorption were measured in control period and during intravenous administration of glycine (G). In normal rats, G produced afferent and efferent dilation, increases in single nephron plasma flow (SNPF) and single nephron glomerular filtration rate (SNGFR) of 24%. Systemic hypertension in HYP rats was associated with increases in transcapillary pressure gradient (delta P) and SNGFR. In this hyperfiltration state, infusion of G did not modify SNGFR of SNPF defining loss of RFR. The antihypertensive treatment was equally effective in normalizing MAP and delta P in CEI and VER, but only CEI rats responded to G with a 20% increase in SNGFR due to an increase in delta P. The most striking findings were that loss of RFR in both HYP and VER rats was associated with a significant decrease in absolute and proximal fractional reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Physiologic adaptations of the tubuloglomerular feedback system

Kidney International, 1990

Knowledge of the existence of a tubuloglomerular feedback system has been available for many year... more Knowledge of the existence of a tubuloglomerular feedback system has been available for many years. Only recently, however, have tenable hypotheses and supporting experimental data become available which have served to provide details regarding the complex inner workings of this system. The facility for examining this integrated physiologic network has derived, in large part, from the routine ability to perform in vivo micropuncture. We anticipate that further advances in this field will hinge on the development of additional experimental techniques to allow cellular biologic aspects of the system to be closely monitored in situ.

Research paper thumbnail of Effect of mesangial cell lysis and proliferation on glomerular hemodynamics in the rat

Kidney International, 1991

To elucidate an involvement of mesangial cells in the regulation of glomerular hemodynamics, rena... more To elucidate an involvement of mesangial cells in the regulation of glomerular hemodynamics, renal micropuncture techniques and glomerular morphometry were employed in Munich-Wistar rats with mesangial cell lytic or proliferative lesions induced by administration of an antibody reactive with Thy-1.1-like antigens on the mesangial cell surface. The antibody-induced mesangial cell lysis at day 1 resulted in a significant decrease in glomerular ultrafiltration coefficient, leading to reduction in single nephron glomerular filtration rate (SNGFR) in spite of a significant increase in both glomerular hydrostatic pressure and single nephron plasma flow (SNPF). During the antibody-induced proliferative lesion at day 6, glomerular ultrafiltration coefficient and SNGFR remained reduced; however, SNPF was now decreased. Morphometric analysis showed the enlargement of capillary luminal volume and the development of new open space in the mesangium accessible for blood flow in the mesangial cell-lytic glomeruli at day 1. An increase in mesangial cell volume was found in the proliferative glomeruli at day 6. The total area of peripheral glomerular basement membrane, presumed as the probable filtration area, was unchanged in these glomeruli. These results indicate that mesangial lesions decrease glomerular ultrafiltration coefficient, and suggest that mesangial cells participate in regulation of glomerular filtration rate.

Research paper thumbnail of Relation of distal tubular NaCl delivery and glomerular hydrostatic pressure

Kidney International, 1972

Relation of distal tubular NaCl delivery and glomerular hydrostatic pressure. We have tested cert... more Relation of distal tubular NaCl delivery and glomerular hydrostatic pressure. We have tested certain aspects of the hypothesis that the rate of distal tubular sodium delivery determines the rate of filtration in that nephron. Schnermann, Wright et al have suggested that a reduction in distal sodium delivery causes the local release of angiotensin which acts to elevate the glomerular hydrostatic

Research paper thumbnail of Combined Effects of Carbonic Anhydrase Inhibitor and Adenosine A<sub>1</sub> Receptor Antagonist on Hemodynamic and Tubular Function in the Kidney

Kidney and Blood Pressure Research, 2007

Background: Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubulogl... more Background: Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubuloglomerular feedback (TGF) and reducing glomerular filtration rate (GFR). Adenosine A 1 receptors (A 1 R) mediate the TGF response and stimulate proximal reabsorption. Methods: Clearance and micropuncture studies were performed in Wistar rats to determine whether blockade of A 1 R (KW3902 0.3 mg/kg i.v.) would prevent CAI (benzolamide 5 mg/kg i.v.) from lowering GFR, whether CAI and KW3902 exert additive effects on sodium excretion, and to what extent such interactions depend on events in the glomerulus, proximal tubule, or distal nephron. Results: KW3902 raised GFR and prevented CAI from lowering GFR. KW3902 and CAI caused additive diuresis and natriuresis. KW3902 and CAI increased lithium clearance, but their effects were redundant. CAI increased the dependence of proximal reabsorption on active chloride transport. KW3902, alone, did likewise, but to a lesser extent than CAI. Adding KW3902 to CAI lessened the shift toward active chloride transport. Conclusions: The data reveal that A 1 R mediate glomerular vascular resistance whether or not TGF is activated, that additive effects of CAI and KW3902 on salt excretion occur, in part, because KW3902 inhibits reab-

Research paper thumbnail of The Chronic Kidney Disease Initiative

Journal of the American Society of Nephrology, 2004

The Chronic Kidney Disease Initiative was implemented at the request of the Council of American K... more The Chronic Kidney Disease Initiative was implemented at the request of the Council of American Kidney Societies to formulate a plan of action to solve many of the perceived problems associated with identifying, caring for, and attaining the best outcomes for patients with chronic kidney disease. With the assistance of a community of stakeholders and a formalized workshop and process, the Chronic Kidney Disease Initiative identified the barriers to solving this complicated problem. Barriers were given hierarchal significance, and solutions and action plans to the barriers were formulated. This article describes the process, the barriers encountered, and the solutions required to fully identify and manage this large and complicated population of patients.

Research paper thumbnail of Aberrant Tubuloglomerular Feedback and HIF-1  Confer Resistance to Ischemia after Subtotal Nephrectomy

Journal of the American Society of Nephrology, 2012

Nephron loss in a diseased kidney invokes adaptations in the remaining nephrons. Whether and how ... more Nephron loss in a diseased kidney invokes adaptations in the remaining nephrons. Whether and how these adaptations condition the response of the kidney to injury is not known. We examined the susceptibility of the kidney after subtotal (5/6th) nephrectomy (STN) to ischemic injury in rats. GFR in STN kidneys did not significantly change after ischemia reperfusion (IR), whereas GFR fell by 70% after IR in unilateral nephrectomy controls. In micropuncture experiments, single-nephron GFR responses mirrored the whole-kidney responses: in STN, single-nephron GFR decreased by 7% after IR compared with 28% in controls. Furthermore, we found that tubuloglomerular feedback, a mechanism that links proximal tubular injury to a fall in GFR, was inoperative in STN but was normal in controls. Restoration of normal feedback in STN attenuated the functional resistance to IR. In addition to the functional resilience, the morphology of the kidney was better preserved in STN. In STN kidneys, the S3 segment of the proximal tubule, normally injured after ischemia, constitutively expressed hypoxia-inducible factor-1a (HIF-1a), which is cytoprotective in ischemia. Inducing HIF before IR improved GFR in control animals, and inhibiting the HIF target hemeoxygenase-1 before IR reduced GFR in STN animals. Taken together, these data suggest that fewer functioning nephrons in a diseased kidney do not increase the susceptibility to injury, but rather, hemodynamic and molecular adaptations in the remnant nephrons precondition them against ischemic injury.

Research paper thumbnail of Glomerular hemodynamics in cell-free and erythrocyte-perfused isolated rat kidney

The American journal of physiology

The cell-free isolated perfused kidney (IPK) is characterized by normal glomerular filtration rat... more The cell-free isolated perfused kidney (IPK) is characterized by normal glomerular filtration rate (GFR) and very low filtration fraction (FF). Addition of erythrocytes to the perfusate (IEPK) increases FF while maintaining &quot;normal&quot; GFR levels. Micropuncture studies were performed in IPK and IEPK to establish the determinants of the glomerular ultrafiltration process responsible for low FF in IPK and to evaluate the impact of the addition of erythrocytes on these determinants. Nephron filtration rate was similar in IPK and IEPK (40 +/- 4 vs. 39 +/- 4 nl/min), whereas nephron perfusate flow was significantly higher in IPK (1,247 +/- 100 vs. 112 +/- 13 nl/min), leading to a superficial nephron FF of 3.4 +/- 0.2% in IPK and 36 +/- 2% in IEPK. Glomerular hydrostatic pressure (PG) and transcapillary hydrostatic pressure gradient (delta P) were 53 +/- 2 and 33 +/- 1 mmHg, respectively, in IPK and 51 +/- 3 and 34 +/- 2 mmHg in IEPK, all normal values. Glomerular arteriolar resistances were significantly lower in IPK than in IEPK, and the glomerular ultrafiltration coefficient (LpA) was significantly lower in IPK (0.053 +/- 0.010 vs. 0.100 +/- 0.020 nl.s-1.mmHg-1), but both values are within the normal in vivo range. These results demonstrate that low FF in IPK is not due to decreased delta P or LpA values but to the high renal perfusion rate required to maintain normal PG and delta P values. Addition of erythrocytes increases glomerular arteriolar resistances and restores glomerular hemodynamics to a pattern nearly identical to in vivo conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: Effect of sodium and salt restriction

Journal of the American Society of Nephrology

Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats,... more Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats, the effect of a low-sodium (LNa) and a low-salt (LNaCl) diet on renal function and on plasma and kidney tissue angiotensin II (AIIp, AIIk) was tested. Clearance experiments were performed in anesthetized rats 7 days after starting on LNa or LNaCl. On a control diet, STZ exhibited an increase in GFR, RBF, and kidney weight (KW) and a reduction in renal vascular resistance (RVR) and AIIk, but no change in AIIp, compared with nondiabetic normal rats (CON). Although sodium restriction reduced and salt restriction increased AIIk in CON, both diets increased AIIp without affecting renal hemodynamics or KW. In diabetic rats, both salt and sodium restriction further increased GFR and RBF by reducing RVR, increased KW, and changed AIIk and AIIp in a similar pattern, but at significantly lower values compared with CON. Daily treatment of STZ-LNa with the AII-receptor blocker losartan (20 mg/L, in drinking water) did not affect the reduction in RVR and the increase in KW but slightly reduced RBF because of a decrease in mean arterial blood pressure and further increased GFR. It was concluded that (1) AIIk but not AIIp is affected differently by LNa compared with LNaCl in both CON and STZ; (2) LNaCl and LNa change AIIp and AIIk in a similar pattern but at significant lower values in STZ compared with CON; and (3) with regard to renal hemodynamics and KW, the response to LNa and LNaCl is different in CON compared with rats 6 wk after the onset of diabetes mellitus, the latter exhibiting a further increase in renal hyperfiltration and KW by a mechanism that is not directly AII receptor dependent.

Research paper thumbnail of Glomerular and tubular interactions between renal adrenergic activity and nitric oxide

The American journal of physiology

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtrat... more Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5-9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3&#39;,5&#39;-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.

Research paper thumbnail of Role of angiotensin in the regulation of renal response to proteins

Seminars in Nephrology

Intrarenal and extrarenal humoral factors have been proposed as mediators and modulators of the r... more Intrarenal and extrarenal humoral factors have been proposed as mediators and modulators of the renal hyperemic response to amino acid infusion. Among the potential modulators, angiotensin II (AII) constitutes the most important candidate due to its critical role in the control of glomerular and tubular function. The modulatory effect of AII has been assessed by (1) measuring the changes in plasma renin activity (PRA)/AII during the normal hyperemic response, and (2) by assessing the levels of PRA/AII and the response to AII-suppressing agents in conditions with no vasodilatory response during amino acid infusion. Administration of a protein load in normal animals or humans does not modify PRA/AII. Absence of a vasodilatory response in various experimental conditions (nitric oxide blockade in normal rats, experimental models of hypertension, diabetes mellitus, chronic glomerulonephritis, cyclosporine administration) is characterized by a significant decrease in proximal tubular reabsorption during amino acid infusion. Converting enzyme inhibitors or AII receptor antagonist restore normal tubular function and the increase in glomerular filtration rate during amino acid infusion. Absence of a vasodilatory response is also associated with increases in kidney AII levels in some of these conditions. These results suggest that (1) AII modulates the amino acid-induced hyperemia through its inhibitory effect on proximal tubular reabsorption and activation of the tubuloglomerular feedback system, and (2) that the expression of the modulatory effect of AII may depend on the interaction between AII and other intrarenal systems like nitric oxide.

Research paper thumbnail of Role of nitric oxide in glomerular physiology and pathophysiology

Advances in nephrology from the Necker Hospital

Research paper thumbnail of Role of nitric oxide in renal hemodynamics

Seminars in Nephrology

Studies performed over the last 10 years have evaluated the role of nitric oxide (NO) in the cont... more Studies performed over the last 10 years have evaluated the role of nitric oxide (NO) in the control of renal hemodynamics. This article reviews the effects of administration of nitric oxide synthase (NOS) blockers on renal function in experimental animals and human volunteers. These studies show that NOS blockade increases renal vascular resistances and decreases the glomerular ultrafiltration coefficient. These experimental studies also support the presence of an important interaction between NO, angiotensin II, and renal nerves in the control of renal function. The use of acute and chronic administration of NOS blockers has generated a great deal of new and exciting information regarding the role of NO in the regulation of normal renal function.

Research paper thumbnail of Physiology of the Renal Circulation

Ascites and Renal Dysfunction in Liver Disease, 2005

Research paper thumbnail of Temporal adjustment of the juxtaglomerular apparatus during sustained inhibition of proximal reabsorption

Journal of Clinical Investigation, 1999

Tubuloglomerular feedback (TGF) stabilizes nephron function by causing changes in single-nephron ... more Tubuloglomerular feedback (TGF) stabilizes nephron function by causing changes in single-nephron GFR (SNGFR) to compensate for changes in late proximal flow (VLP). TGF responds within seconds and reacts over a narrow range of VLP that surrounds normal VLP. To accommodate sustained increases in VLP, TGF must reset around the new flow. We studied TGF resetting by inhibiting proximal reabsorption with benzolamide (BNZ; administered repeatedly over a 24-hour period) in Wistar-Froemter rats. BNZ acutely activates TGF, thereby reducing SNGFR. Micropuncture was performed 6-10 hours after the fourth BNZ dose, when diuresis had subsided. BNZ caused glomerular hyperfiltration, which was prevented with inhibitors of macula densa nitric oxide synthase (NOS). Because of hyperfiltration, BNZ increased VLP and distal flow, but did not affect the basal TGF stimulus (early distal salt concentration). BNZ slightly blunted normalized maximum TGF response and the basal state of TGF activation. BNZ sensitized SNGFR to reduction by S-methyl-thiocitrulline (SMTC) and caused the maximum TGF response to be strengthened by SMTC. Sensitization to type I NOS (NOS-I) blockers correlated with increased macula densa NOS-I immunoreactivity. Tubular transport measurements confirmed that BNZ affected TGF within the juxtaglomerular apparatus. During reduced proximal reabsorption, TGF resets to accommodate increased flow and SNGFR through a mechanism involving macula densa NOS.

Research paper thumbnail of The Renal Response to Sepsis and the Role of NOS Isoforms

The clinical syndrome of sepsis is characterized by the conjunction of systemic hypotension and m... more The clinical syndrome of sepsis is characterized by the conjunction of systemic hypotension and multiorgan failure leading to high morbidity and mortality . The reduction in systemic blood pressure is primarily the result of generation of excess nitric oxide by cytokine dependent transcription of inducible nitric oxide synthase . However, the failure of various organs, particularly renal dysfunction, is not merely the consequence of systemic hypotension, but rather results from vasoconstriction resulting in a marked reduction in glomerular~ltration rate . The question, therefore, arises "Why, if systemic hypotension is the result of generation of the vasodilator, NO, does renal vasoconstriction and renal failure occur?" There must be speci~c mechanisms which exclude the kidney, and potentially other organs, from sharing in the more generalized reduction in vascular resistance. Renal failure considerably complicates the treatment of the sepsis syndrome and therefore this apparent pathophysiologic enigma requires further investigation.

Research paper thumbnail of An analysis of renal nitric oxide contribution to hyperfiltration in diabetic rats

Journal of Laboratory and Clinical Medicine, 2001

Research paper thumbnail of Adenosine A<sub>1</sub> Receptors Determine Glomerular Hyperfiltration and the Salt Paradox in Early Streptozotocin Diabetes Mellitus

Research paper thumbnail of Glycine Prevents Toxic Tubular Cell Injury

Renal Failure, 1994

Glycine prevents tubular injury as suggested by in vitro cell culture studies, studies in the iso... more Glycine prevents tubular injury as suggested by in vitro cell culture studies, studies in the isolated perfused kidney, and in vivo studies. We have previously demonstrated that intratubular administration of uranyl nitrate (UN) produces proximal tubular cell injury and decreases proximal tubular reabsorption (APR). The decrease in APR activates tubuloglomerular feedback and lowers nephron filtration rate (SNGFR). This study was designed to evaluate if glycine administration could prevent the decrease in SNGFR after UN administration and if maintenance of SNGFR was due to tubular cell cytoprotection or suppression of the tubuloglomerular feedback. Administration of 0.65 ng of UN into the early proximal tubule was associated with a decrease in distal SNGFR (SNGFRD) from 29 +/- 2 to 24 +/- 2 nL/min (p &lt; .05) and late proximal SNGFR (SNGFRLP) from 37 +/- 2 to 26 +/- 2 nL/min, and APR from 14 +/- 1 to 10 +/- 1 nL/min. Systemic administration of glycine (20 g/dL, 1.4 mL/h) was associated with significant increases in SNGFRD and SNGFRLP, and APR (38 +/- 3, 44 +/- 3, and 15 +/- 2 nL/min). UN administration did not affect APR or SNGFR in glycine-treated rats. These findings demonstrate that glycine prevents UN-induced decreases in SNGFR through a cytoprotective effect on proximal tubular cells.

Research paper thumbnail of Vascular contributions to pathogenesis of acute renal failure

Renal Failure, 1998

ABSTRACT

Research paper thumbnail of Renal functional reserve in treated and untreated hypertensive rats

Kidney International, 1991

Renal functional reserve (renal response to protein loading, RFR) has been suggested as a method ... more Renal functional reserve (renal response to protein loading, RFR) has been suggested as a method to verify the presence of hyperfiltration. This study was designed to evaluate the role of RFR as an indicator of increased glomerular capillary hydrostatic pressure in short-term treated and untreated rats with two-kidney, one-clip Goldblatt hypertension. One month after placing a silver clip, micropuncture studies were performed on the unclipped kidney. Normal rats and three groups of clipped rats [untreated group (HYP), a group treated with captopril (CEI) and a group treated with verapamil (VER) 5 days before the micropuncture studies] were studied. Glomerular hemodynamics and proximal tubular reabsorption were measured in control period and during intravenous administration of glycine (G). In normal rats, G produced afferent and efferent dilation, increases in single nephron plasma flow (SNPF) and single nephron glomerular filtration rate (SNGFR) of 24%. Systemic hypertension in HYP rats was associated with increases in transcapillary pressure gradient (delta P) and SNGFR. In this hyperfiltration state, infusion of G did not modify SNGFR of SNPF defining loss of RFR. The antihypertensive treatment was equally effective in normalizing MAP and delta P in CEI and VER, but only CEI rats responded to G with a 20% increase in SNGFR due to an increase in delta P. The most striking findings were that loss of RFR in both HYP and VER rats was associated with a significant decrease in absolute and proximal fractional reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Physiologic adaptations of the tubuloglomerular feedback system

Kidney International, 1990

Knowledge of the existence of a tubuloglomerular feedback system has been available for many year... more Knowledge of the existence of a tubuloglomerular feedback system has been available for many years. Only recently, however, have tenable hypotheses and supporting experimental data become available which have served to provide details regarding the complex inner workings of this system. The facility for examining this integrated physiologic network has derived, in large part, from the routine ability to perform in vivo micropuncture. We anticipate that further advances in this field will hinge on the development of additional experimental techniques to allow cellular biologic aspects of the system to be closely monitored in situ.

Research paper thumbnail of Effect of mesangial cell lysis and proliferation on glomerular hemodynamics in the rat

Kidney International, 1991

To elucidate an involvement of mesangial cells in the regulation of glomerular hemodynamics, rena... more To elucidate an involvement of mesangial cells in the regulation of glomerular hemodynamics, renal micropuncture techniques and glomerular morphometry were employed in Munich-Wistar rats with mesangial cell lytic or proliferative lesions induced by administration of an antibody reactive with Thy-1.1-like antigens on the mesangial cell surface. The antibody-induced mesangial cell lysis at day 1 resulted in a significant decrease in glomerular ultrafiltration coefficient, leading to reduction in single nephron glomerular filtration rate (SNGFR) in spite of a significant increase in both glomerular hydrostatic pressure and single nephron plasma flow (SNPF). During the antibody-induced proliferative lesion at day 6, glomerular ultrafiltration coefficient and SNGFR remained reduced; however, SNPF was now decreased. Morphometric analysis showed the enlargement of capillary luminal volume and the development of new open space in the mesangium accessible for blood flow in the mesangial cell-lytic glomeruli at day 1. An increase in mesangial cell volume was found in the proliferative glomeruli at day 6. The total area of peripheral glomerular basement membrane, presumed as the probable filtration area, was unchanged in these glomeruli. These results indicate that mesangial lesions decrease glomerular ultrafiltration coefficient, and suggest that mesangial cells participate in regulation of glomerular filtration rate.

Research paper thumbnail of Relation of distal tubular NaCl delivery and glomerular hydrostatic pressure

Kidney International, 1972

Relation of distal tubular NaCl delivery and glomerular hydrostatic pressure. We have tested cert... more Relation of distal tubular NaCl delivery and glomerular hydrostatic pressure. We have tested certain aspects of the hypothesis that the rate of distal tubular sodium delivery determines the rate of filtration in that nephron. Schnermann, Wright et al have suggested that a reduction in distal sodium delivery causes the local release of angiotensin which acts to elevate the glomerular hydrostatic

Research paper thumbnail of Combined Effects of Carbonic Anhydrase Inhibitor and Adenosine A<sub>1</sub> Receptor Antagonist on Hemodynamic and Tubular Function in the Kidney

Kidney and Blood Pressure Research, 2007

Background: Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubulogl... more Background: Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubuloglomerular feedback (TGF) and reducing glomerular filtration rate (GFR). Adenosine A 1 receptors (A 1 R) mediate the TGF response and stimulate proximal reabsorption. Methods: Clearance and micropuncture studies were performed in Wistar rats to determine whether blockade of A 1 R (KW3902 0.3 mg/kg i.v.) would prevent CAI (benzolamide 5 mg/kg i.v.) from lowering GFR, whether CAI and KW3902 exert additive effects on sodium excretion, and to what extent such interactions depend on events in the glomerulus, proximal tubule, or distal nephron. Results: KW3902 raised GFR and prevented CAI from lowering GFR. KW3902 and CAI caused additive diuresis and natriuresis. KW3902 and CAI increased lithium clearance, but their effects were redundant. CAI increased the dependence of proximal reabsorption on active chloride transport. KW3902, alone, did likewise, but to a lesser extent than CAI. Adding KW3902 to CAI lessened the shift toward active chloride transport. Conclusions: The data reveal that A 1 R mediate glomerular vascular resistance whether or not TGF is activated, that additive effects of CAI and KW3902 on salt excretion occur, in part, because KW3902 inhibits reab-

Research paper thumbnail of The Chronic Kidney Disease Initiative

Journal of the American Society of Nephrology, 2004

The Chronic Kidney Disease Initiative was implemented at the request of the Council of American K... more The Chronic Kidney Disease Initiative was implemented at the request of the Council of American Kidney Societies to formulate a plan of action to solve many of the perceived problems associated with identifying, caring for, and attaining the best outcomes for patients with chronic kidney disease. With the assistance of a community of stakeholders and a formalized workshop and process, the Chronic Kidney Disease Initiative identified the barriers to solving this complicated problem. Barriers were given hierarchal significance, and solutions and action plans to the barriers were formulated. This article describes the process, the barriers encountered, and the solutions required to fully identify and manage this large and complicated population of patients.

Research paper thumbnail of Aberrant Tubuloglomerular Feedback and HIF-1  Confer Resistance to Ischemia after Subtotal Nephrectomy

Journal of the American Society of Nephrology, 2012

Nephron loss in a diseased kidney invokes adaptations in the remaining nephrons. Whether and how ... more Nephron loss in a diseased kidney invokes adaptations in the remaining nephrons. Whether and how these adaptations condition the response of the kidney to injury is not known. We examined the susceptibility of the kidney after subtotal (5/6th) nephrectomy (STN) to ischemic injury in rats. GFR in STN kidneys did not significantly change after ischemia reperfusion (IR), whereas GFR fell by 70% after IR in unilateral nephrectomy controls. In micropuncture experiments, single-nephron GFR responses mirrored the whole-kidney responses: in STN, single-nephron GFR decreased by 7% after IR compared with 28% in controls. Furthermore, we found that tubuloglomerular feedback, a mechanism that links proximal tubular injury to a fall in GFR, was inoperative in STN but was normal in controls. Restoration of normal feedback in STN attenuated the functional resistance to IR. In addition to the functional resilience, the morphology of the kidney was better preserved in STN. In STN kidneys, the S3 segment of the proximal tubule, normally injured after ischemia, constitutively expressed hypoxia-inducible factor-1a (HIF-1a), which is cytoprotective in ischemia. Inducing HIF before IR improved GFR in control animals, and inhibiting the HIF target hemeoxygenase-1 before IR reduced GFR in STN animals. Taken together, these data suggest that fewer functioning nephrons in a diseased kidney do not increase the susceptibility to injury, but rather, hemodynamic and molecular adaptations in the remnant nephrons precondition them against ischemic injury.