scholarly journals Glomerular Hyperfiltration in Experimental Diabetes Mellitus

1999 ◽  
Vol 10 (12) ◽  
pp. 2569-2576
Author(s):  
VOLKER VALLON ◽  
KERSTIN RICHTER ◽  
ROLAND C. BLANTZ ◽  
SCOTT THOMSON ◽  
HARTMUT OSSWALD
Keyword(s):  
Diabetes Mellitus ◽  
Distal Tubule ◽  
Diabetic Rats ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Glomerular Hyperfiltration ◽  
Feedback Signal ◽  
Early Diabetes ◽  
Nondiabetic Control ◽  
Single Nephron

Abstract. An increase in Na+/glucose cotransport upstream to the macula densa might contribute to the increase in single nephron GFR (SNGFR) in early diabetes mellitus by lowering the signal of the tubuloglomerular feedback, i.e., the luminal Na+, Cl-, and K+ concentration sensed by the macula densa. To examine this issue, micropuncture experiments were performed in nephrons with superficial glomeruli of streptozotocin-induced diabetes mellitus in rats. First, in nondiabetic control rats, ambient early distal tubular concentrations of Na+, Cl-, and K+ were about 21, 20, and 1.2 mM, respectively, suggesting collection sites relatively close to the macula densa. Second, glomerular hyperfiltration in diabetic rats was associated with a reduction in ambient early distal tubular concentrations of Na+, Cl-, and K+ by 20 to 28%, reflecting an increase in fractional reabsorption of these ions up to the early distal tubule. Third, in diabetic rats, early proximal tubular application of phlorizin, an inhibitor of Na+/glucose cotransport, elicited (1) a greater reduction in absolute and fractional reabsorption of Na+, Cl-, and K+ up to the early distal tubule, and (2) a greater increase in early distal tubular concentration of these ions, which was associated with a more pronounced reduction in SNGFR. These findings support the concept that stimulation of tubular Na+/glucose cotransport by reducing the tubuloglomerular feedback signal at the macula densa may contribute to glomerular hyperfiltration in diabetic rats. Glomerular hyperfiltration in diabetic rats serves to compensate for the rise in fractional tubular reabsorption to partly restore the electrolyte load to the distal nephron.

Glomerulotubular balance, dietary protein, and the renal response to glycine in diabetic rats

2002 ◽  
Vol 282 (4) ◽  
pp. R1096-R1103 ◽  
Author(s):  
Larry A. Slomowitz ◽  
Aihua Deng ◽  
John S. Hammes ◽  
Francis Gabbai ◽  
Scott C. Thomson
Keyword(s):  
Dietary Protein ◽  
Distal Tubule ◽  
Diabetic Rats ◽  
Tubular Reabsorption ◽  
Protein Restriction ◽  
Tubuloglomerular Feedback ◽  
Vascular Effect ◽  
Dietary Protein Restriction ◽  
Single Nephron ◽  
Renal Micropuncture

The glomerular filtration rate (GFR) normally increases during glycine infusion, which is a test of “renal reserve.” Renal reserve is absent in diabetes mellitus. GFR increases after protein feeding because of increased tubular reabsorption, which reduces the signal for tubuloglomerular feedback (TGF). Dietary protein restriction normalizes some aspects of glomerular function in diabetes. Renal micropuncture was performed in rats 4–5 wk after diabetes was induced by streptozotocin to determine whether renal reserve is lost as a result of altered tubular function and activation of TGF, whether 10 days of dietary protein restriction could restore renal reserve, and whether this results from effects of glycine on the tubule. TGF activation was determined by locating single-nephron GFR (SNGFR) in the early distal tubule along the TGF curve. The TGF signal was determined from the ionic content of the early distal tubule. In nondiabetic rats, SNGFR in the early distal tubule increased during glycine infusion because of primary vasodilation augmented by increased tubular reabsorption, which stabilized the TGF signal. In diabetic rats, glycine reduced reabsorption, thereby activating TGF, which was largely responsible for the lack of renal reserve. In protein-restricted diabetic rats, the tubular response to glycine remained abnormal, but renal reserve was restored by a vascular mechanism. Glycine affects GFR directly and via the tubule. In diabetes, reduced tubular reabsorption dominates. In low-protein diabetes, the vascular effect is enhanced and overrides the effect of reduced tubular reabsorption.

Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus

1991 ◽  
Vol 260 (6) ◽  
pp. F946-F952 ◽  
Author(s):  
C. A. Pollock ◽  
J. R. Lawrence ◽  
M. J. Field
Keyword(s):  
Diabetes Mellitus ◽  
Tubuloglomerular Feedback ◽  
Sprague Dawley ◽  
Osmotic Diuresis ◽  
Early Diabetes ◽  
Diabetic State ◽  
Severe Diabetes ◽  
Single Nephron ◽  
The Difference ◽  
Moderate Diabetes

Tubular Na handling and tubuloglomerular feedback (TGF) activity were assessed using micropuncture techniques during the hyperfiltration phase of streptozotocin-induced diabetes mellitus in Sprague-Dawley rats. Three animal groups were studied, designated as having severe diabetes [blood sugar level (BSL) 18-25 mmol/l], moderate diabetes (BSL 13-18 mmol/l) and control (BSL less than 10 mmol/l). Single-nephron glomerular filtration rate (SNGFR) measured at both late proximal (LP) and early distal (ED) sites was elevated in severe diabetes compared with both other groups. TGF activity, determined as the difference between LP and ED measurements of SNGFR, was significantly increased in severe diabetes (46.4 +/- 6.6 vs. 30.1 +/- 6.5 vs. 14.8 +/- 1.9 nl/min). Tubular Na transport was higher in severe diabetes compared with control, as demonstrated by a decrease in fractional delivery of Na to the LP (42.9 +/- 3.0 vs. 52.9 +/- 1.9%), as well as to the ED site (4.5 +/- 0.4 vs. 12.3 +/- 0.9%). Administration of phlorizin to severely diabetic animals resulted in a BSL comparable to that observed in moderate diabetes, and whole animal GFR, as well as SNGFR, TGF activity, and tubular Na handling were also similar to those found in moderate diabetes. Studies performed during mannitol infusion demonstrated that osmotic diuresis alone was not associated with the changes in TGF and tubular Na handling observed in the diabetic state. These data suggest that the hyperfiltration occurring in early diabetes is associated with enhanced proximal and loop resorption of Na independent of Na-glucose cotransport and osmotic diuresis. Activation of TGF serves to limit the rise in GFR, which results from factors as yet unrecognized in the diabetic state.

p22phox in the macula densa regulates single nephron GFR during angiotensin II infusion in rats

2007 ◽  
Vol 292 (4) ◽  
pp. H1685-H1689 ◽  
Author(s):  
Pouneh Nouri ◽  
Pritmohinder Gill ◽  
Min Li ◽  
Christopher S. Wilcox ◽  
William J. Welch
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Blood Pressure Response ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Distal Tubule ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Ang Ii ◽  
Renal Vasoconstriction ◽  
Single Nephron

Angiotensin II (ANG II) infusion increases renal superoxide (O2−) and enhances renal vasoconstriction via macula densa (MD) regulation of tubuloglomerular feedback, but the mechanism is unclear. We targeted the p22 phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with small-interfering RNA (siRNA) to reduce NADPH oxidase activity and blood pressure response to ANG II in rats. We compared single nephron glomerular filtration rate (SNGFR) in samples collected from the proximal tubule (PT), which interrupts delivery to the MD, and from the distal tubule (DT), which maintains delivery to the MD, to assess MD regulation of GFR. SNGFR was measured in control and ANG II-infused rats (200 ng·kg−1·min−1 for 7 days) 2 days after intravenous injection of vehicle or siRNA directed to p22 phox to test the hypothesis that p22 phox mediates MD regulation of SNGFR during ANG II. The regulation of SNGFR by MD, determined by PT SNGFR-DT SNGFR, was not altered by siRNA in control rats (control + vehicle, 13 ± 1, n = 8; control + siRNA, 12 ± 2 nl/min, n = 8; not significant) but was reduced by siRNA in ANG II-treated rats (ANG II + vehicle, 13 ± 2, n = 7; ANG II + siRNA, 7 ± 1 nl/min, n = 8; P < 0.05). We conclude that p22 phox and NADPH oxidase regulate the SNGFR during ANG II infusion via MD-dependent mechanisms.

Early diabetes as a model for testing the regulation of juxtaglomerular NOS I

2004 ◽  
Vol 287 (4) ◽  
pp. F732-F738 ◽  
Author(s):  
Scott C. Thomson ◽  
Aihua Deng ◽  
Norikuni Komine ◽  
John S. Hammes ◽  
Roland C. Blantz ◽  
...  
Keyword(s):  
Diabetic Rats ◽  
Tubuloglomerular Feedback ◽  
Early Diabetes ◽  
Henle's Loop ◽  
Single Nephron ◽  
Streptozotocin Diabetic Rats ◽  
Flow Through ◽  
Oxide Synthase ◽  
Subsequent Addition

Dysregulation of kidney nitric oxide synthase (NOS) I may alter renal hemodynamics in diabetes. Four types of studies were performed in anesthetized 1- to 2-wk-streptozotocin diabetic rats. 1) Glomerular filtration rate (GFR) was measured before and during NOS I blockade. Subsequent addition of nonspecific NOS blocker tested for residual NO from other isoforms. Acute systemic NOS I blockade reduced GFR only in diabetics. Nonspecific NOS blockade had no additional effect on NOS I-blocked diabetics. 2) Renal blood flow (RBF) was monitored for evidence that tubuloglomerular feedback (TGF) resets during 1 h of continuous activation with benzolamide. NOS I blockade was added to test for the role of NOS I in TGF resetting. During 1 h of TGF activation in controls, RBF initially declined and then returned to baseline. In diabetic and NOS I-blocked rats, RBF declined and remained low. 3) The ability of NOS I blockade to increase the homeostatic efficiency of TGF in diabetes was tested by micropuncture in free-flowing nephrons. The addition of NOS I blocker to the tubular fluid increased TGF efficiency in control and diabetic rats. 4) The influence of distal salt delivery on local NOS I activity was tested by micropuncture. Henle's loop was perfused at varying rates with NOS I blocker while single-nephron GFR (SNGFR) from the late proximal tubule was measured. In controls, NOS I blockade mainly reduced SNGFR when flow through Henle's loop was high. In diabetics, NOS I blockade reduced SNGFR independently of flow through Henle's loop. In conclusion, normally, salt delivered to the macula densa (MD) exerts immediate control over MD NOS I activity. In diabetes, there is ongoing overactivity of NOS I that is not regulated by MD salt.

scholarly journals Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

2019 ◽  
Vol 30 (4) ◽  
pp. 578-593 ◽  
Author(s):  
Jie Zhang ◽  
Jin Wei ◽  
Shan Jiang ◽  
Lan Xu ◽  
Lei Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Knockout Mice ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Glomerular Hyperfiltration ◽  
Early Diabetes

BackgroundGlomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)–dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR.MethodsWe used microperfusion, micropuncture, and renal clearance of FITC–inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa–specific NOS1 knockout mice.ResultsAcute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa–specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR.ConclusionsWe identified a novel mechanism of acute hyperglycemia–induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.

Effect of long- and short-term antidiuretic hormone availability on internephron heterogeneity in the adult rat

1984 ◽  
Vol 246 (6) ◽  
pp. F879-F888 ◽  
Author(s):  
M. M. Trinh-Trang-Tan ◽  
N. Bouby ◽  
M. Doute ◽  
L. Bankir
Keyword(s):  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Feedback Signal ◽  
Short Term ◽  
Adult Rat ◽  
Single Nephron ◽  
Proximal Tubular ◽  
Hereditary Diabetes ◽  
Kidney Maturation ◽  
Acute Changes

We have previously shown that certain aspects of internephron heterogeneity are reduced or absent in Brattleboro rats with hereditary diabetes insipidus (DI) lacking ADH and can be restored by long-term ADH administration started before complete kidney maturation. In the present study, the effects of long- and short-term availability of ADH in adulthood were studied in Brattleboro DI rats. Single nephron glomerular filtration rate (SNGFR), glomerular volume (GV), and proximal tubular length (PTL) were measured in superficial and juxtamedullary nephrons using the ferrocyanide and microdissection techniques. ADH administration for 6 wk in adult DI rats (group A) restored normal nephron heterogeneity of SNGFR, GV, and PTL by increasing the filtration and size of deep nephrons. Acute changes in ADH availability induced either by 1-h ADH infusion in DI rats (group C) or by ADH discontinuation for 2 days in treated DI rats (group D) did not significantly change the anatomical parameters and only moderately affected SNGFR compared with the preexisting states (groups B and A, respectively). These results suggest that the influence of ADH on internephron heterogeneity is initiated by an increase in deep nephron SNGFR. Based on recent findings concerning the effects of ADH on the medullary (M) part of the thick ascending limbs (TAL), we suggest that the increase in deep nephron SNGFR after ADH may be due to a change in the tubuloglomerular feedback signal at the macula densa resulting from ADH-induced stimulation of the solute reabsorption in the MTAL. Superficial nephrons would be less sensitive to this change due to their long cortical TAL, which removes the macula densa further from the MTAL and provides additional sites for solute reabsorption.

Micropuncture analysis of single-nephron function in NHE3-deficient mice

1999 ◽  
Vol 277 (3) ◽  
pp. F447-F453 ◽  
Author(s):  
John N. Lorenz ◽  
Patrick J. Schultheis ◽  
Timothy Traynor ◽  
Gary E. Shull ◽  
Jürgen Schnermann
Keyword(s):  
Proximal Tubule ◽  
Filtration Rate ◽  
Distal Tubule ◽  
Transport Processes ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Fluid Reabsorption ◽  
Fluid Delivery ◽  
Single Nephron ◽  
Flow Pressure

The Na/H exchanger isoform 3 (NHE3) is expressed in the proximal tubule and thick ascending limb and contributes to the reabsorption of fluid and electrolytes in these segments. The contribution of NHE3 to fluid reabsorption was assessed by micropuncture in homozygous ( Nhe3 −/−) and heterozygous ( Nhe3 +/−) knockout mice, and in their wild-type (WT, Nhe3 +/+) littermates. Arterial pressure was lower in the Nhe3 −/−mice (89 ± 6 mmHg) compared with Nhe3 +/+ (118 ± 4) and Nhe3 +/−(108 ± 5). Collections from proximal and distal tubules demonstrated that proximal fluid reabsorption was blunted in both Nhe3 +/− and Nhe3 −/−mice (WT, 4.2 ± 0.3; Nhe3 +/−, 3.4 ± 0.2; and Nhe3 −/−, 2.6 ± 0.3 nl/min; P < 0.05). However, distal delivery of fluid was not different among the three groups of mice (WT, 3.3 ± 0.4 nl/min; Nhe3 +/−, 3.3 ± 0.2 nl/min; and Nhe3 −/−, 3.0 ± 0.4 nl/min; P < 0.05). In Nhe3 −/−mice, this compensation was largely attributable to decreased single-nephron glomerular filtration rate (SNGFR): 10.7 ± 0.9 nl/min in the Nhe3 +/+ vs. 6.6 ± 0.8 nl/min in the Nhe3 −/−, measured distally. Proximal-distal SNGFR differences in Nhe3 −/−mice indicated that much of the decrease in SNGFR was due to activation of tubuloglomerular feedback (TGF), and measurements of stop-flow pressure confirmed that TGF is intact in Nhe3 −/−animals. In contrast to Nhe3 −/−mice, normalization of early distal flow rate in Nhe3 +/−mice was not related to decreased SNGFR (9.9 ± 0.7 nl/min), but rather, to increased fluid reabsorption in the loop segment ( Nhe3 +/+, 2.6 ± 0.2; Nhe3 +/−, 3.6 ± 0.5 nl/min). We conclude that NHE3 is a major Na/H exchanger isoform mediating Na+ and fluid reabsorption in the proximal tubule. In animals with NHE3 deficiency, normalization of fluid delivery to the distal tubule is achieved through alterations in filtration rate and/or downstream transport processes.

Tubuloglomerular feedback and tubular reabsorption during acute potassium loading in rats

1994 ◽  
Vol 267 (2) ◽  
pp. F223-F230 ◽  
Author(s):  
B. Braam ◽  
P. Boer ◽  
H. A. Koomans
Keyword(s):  
Distal Tubule ◽  
Plasma Potassium ◽  
Tubuloglomerular Feedback ◽  
Control Group ◽  
Sprague Dawley ◽  
Time Control ◽  
Sprague Dawley Rats ◽  
Single Nephron ◽  
Flow Pressure ◽  
Potassium Loading

Acute hyperkalemia has been associated with changes in reabsorption, glomerular filtration rate (GFR), and autoregulation, which might represent altered tubuloglomerular feedback (TGF) responsiveness. Therefore, TGF responsiveness, segmental reabsorption of water, sodium and potassium, and single-nephron GFR were evaluated during acute potassium loading in male Sprague-Dawley rats. Rats receiving 300 mM KNO3, KHCO3, and KCl showed significantly increased plasma potassium levels and attenuation of stop-flow pressure responses 45-90 min after starting the potassium infusion compared with that observed in time controls and rats infused with 300 mM NaCl. Attenuation of TGF responsiveness could not be related to plasma and kidney angiotensin II levels. Segmental water and sodium handling and proximal to distal single-nephron GFR differences assessed in a time control group and a group receiving 300 mM KCl revealed no changes related to KCl infusion. However, late proximal and early distal potassium concentrations increased significantly from 4.7 +/- 0.2 to 6.3 +/- 0.3 mM (P < 0.01) and from 1.5 +/- 0.1 to 2.7 +/- 0.4 mM (P < 0.01), respectively. In summary, although attenuated TGF responsiveness was demonstrated at higher perfusion rates, this study does not support a significant role for either the TGF mechanism or changes in reabsorption upstream of the early distal tubule for the initiation of kaliuresis during acute potassium loading.

scholarly journals Effect of Fenugreek (Methi) on Cortical Thickness of the Thymus in Streptozotocin-Induced Diabetic Rats

1970 ◽  
Vol 7 (1) ◽  
pp. 37-41
Author(s):  
DK Mondal ◽  
MMA Moinuddin ◽  
MM Saha ◽  
AM Khanom ◽  
BMA Yousuf ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cortical Thickness ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Control Group ◽  
Key Words Diabetes Mellitus ◽  
Key Words Diabetes ◽  
Nondiabetic Control ◽  
The Mean ◽  
Long Evans

Objective: To find out microscopically whether Trigonella foenumgraecum (fenugreek seeds/methi seeds) has got any preventive role against the lowering of cortical thickness of the thymic lobules in diabetes mellitus. Design: An experimental study on Long Evans rats which were divided into three equal groups depending on their different shorts of dietary feeding and drug treatment. Setting: Anatomy department of IPGMR (Institute of Post Graduate Medicine and Research) at present BSMMU (Bangabandhu Sheikh Mujib Medical University) and BIRDEM (Bangladesh Institute of Research and Rehabilitation in diabetes, Endocrine & Metabolic Disorders). Subjects: Fifty eight healthy young Long Evans rats of either sex weighing 72 to 174gm aged between 50 to 60 days were used in this study. Main outcome measures: Variation of cortical thickness of the thymic lobules in different groups of rat. Result: Cortical thickness in the nondiabetic control group, which ranges from 30.17 to 36.99. and the mean was 34.83 ± 0.60. In diabetic control group the cortical thickness ranges from 17.78 to 26.46 and the mean was 21.85 ± 1 On the other hand, in the fenugreek- treated diabetic rats the cortical thickness ranges from 25.71 to 32.95 and mean cortical thickness was 30.49 ± 0.75. Conclusion: Fenugreek showed a tendency of acting against lowering of the cortical thickness of the thymic lobule of Streptozotocin-induced diabetes mellitus. However, further investigations are recommended for establishing fenugreek as a safe, useful effective agent to preserve the cortical thickness improving the diabetic condition by acting as antidiabetogenic agent. Key words: Diabetes mellitus, Differential lymphocyte count, Fenugreek, Thymus   doi: 10.3329/bja.v7i1.3017 Bangladesh Journal of Anatomy January 2009, Vol. 7 No. 1 pp. 37-41

Ecto-5′-nucleotidase (cd73)-dependent and -independent generation of adenosine participates in the mediation of tubuloglomerular feedback in vivo

2006 ◽  
Vol 291 (2) ◽  
pp. F282-F288 ◽  
Author(s):  
Dan Yang Huang ◽  
Volker Vallon ◽  
Herbert Zimmermann ◽  
Patricia Koszalka ◽  
Jürgen Schrader ◽  
...  
Keyword(s):  
Atp Release ◽  
Distal Tubule ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Local Formation ◽  
Normal Fluid ◽  
Sequence Of Events ◽  
Arterial Blood ◽  
Normal Mean

Tubuloglomerular feedback (TGF) describes a sequence of events linking salt concentrations in tubular fluid at the macula densa to the vascular tone of the afferent arteriole and thus to the glomerular filtration rate (GFR) of the same nephron. The signal transduction pathways of TGF remain incompletely understood, but both ATP release from macula densa cells and local formation of adenosine were suggested to be involved in the process. To test the role of extracellular formation of adenosine by ecto-5′-nucleotidase (cd73) in TGF, in regulation of GFR, and in tubular reabsorption, renal clearance and micropunture experiments were performed in cd73 wild-type (cd73+/+) and knockout mice (cd73−/−). The cd73−/− mice presented normal mean arterial blood pressure, but modestly lower whole kidney and single nephron GFR (SNGFR). Fractional reabsorption of Na+ and K+ up to the late proximal tubule, distal tubule, as well as urine were not significantly different between cd73−/− and cd73+/+ mice. Lack of cd73 resulted in a diminished TGF response, as indicated by smaller changes of stop-flow pressure in response to increasing loop of Henle perfusion from 0 to 25 nl/min, smaller differences in SNGFR determined from paired proximal and distal tubular collections, and by smaller fractional changes of distal SNGFR in response to adding 6 nl/min of artificial tubular fluid to free-flowing proximal tubules. The TGF response in cd73+/+ mice and the residual TGF response in cd73−/− mice were completely inhibited by adenosine A1-receptor blockade. The results suggest that extracellular formation of adenosine by ecto-5′-nucleotidase (cd73) is dispensable for normal fluid, Na+, or K+ reabsorption along the nephron, but contributes to the regulation of GFR. Adenosine generated by both ecto-5′-nucleotidase (cd73)-dependent and -independent mechanisms participates in the mediation of TGF in vivo.

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