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Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.

Purpose of reviewThe purpose of this review is to correlate predictions based on pre-clinical data with outcomes from clinical trials that examine the effects of incretin-based diabetes treatments on the kidney. The incretin-based treatments include agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of the enzyme, dipeptidyl peptidase-4 (DPP-4). In addition, what is known about the incretin-based therapies will be compared to what is known about the renal effects of SGLT2 inhibitors.Recent findingsLarge-scale clinical trials have shown that SGLT2 inhibitors reduce albuminuria and preserve estimated glomerular filtration rate (eGFR) in patients with diabetic nephropathy. A concise and plausible hemodynamic mechanism is supported by pre-clinical research on the physiology and pharmacology of SGLT2. Large-scale clinical trials have shown that incretin-based therapies mitigate albuminuria but have not shown beneficial effects on eGFR. Research on the incretin-based therapies has yielded a diverse array of direct effects throughout the body, which fuels speculation as to how these drugs might benefit the diabetic kidney and affect its function(s). But in vivo experiments have yet to confirm that the proposed mechanisms underlying emergent phenomena, such as proximal tubular fluid reabsorption, are the ones predicted by cell and molecular experiments. There may be salutary effects of incretin-based treatments on the diabetic kidney, but the system is complex and not amenable to simple explanation or prior prediction. This contrasts with the renal effects of SGLT2 inhibitors, which can be explained concisely.

Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ∼80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ∼80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney's demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are also uricosuric. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

Diabetic nephropathy is the commonest cause of end-stage renal disease. Inordinate kidney growth and glomerular hyperfiltration at the very early stages of diabetes are putative antecedents to this disease. The kidney is the only organ that grows larger with the onset of diabetes mellitus, yet there remains confusion about the mechanism and significance of this growth. Here we show that kidney proximal tubule cells in culture transition to senescence in response to oxidative stress. We further determine the temporal expression of [G.sub.1] phase cell cycle components in rat kidney cortex at days 4 and 10 of streptozotocin diabetes to evaluate changes in this growth response. In diabetic rats we observe increases in kidney weight-to-body weight ratios correlating with increases in expression of the growth-related proteins in the kidney at day 4 after induction of diabetes. However, at day 10 we find a decrease in this profile in diabetic animals coincident with increased cyclin-dependent kinase inhibitor expressions. We observe no change in caspase-3 expression in the diabetic kidneys at these early time points; however, diabetic animals demonstrate reduced kidney connexin 43 and increased plasminogen activator inhibitor-I expressions and increased senescence-associated 13-galactosidase activity in cortical tubules. In summary, diabetic kidneys exhibit an early temporal induction of growth phase components followed by their suppression concurrent with the induction of cyclin-dependent kinase inhibitors and markers of senescence. These data delineate a phenotypic change in cortical tubules early in the pathogenesis of diabetes that may contribute to further downstream complications of the disease. proximal tubule; hypertrophy; cyclin-dependent kinase inhibitor; connexin 43 doi: 10.1152/ajpcell.00096.2010.

After subtotal nephrectomy (STN), the remaining nephrons engage in hyperfiltration, which may be facilitated by a reduced sensitivity of the tubuloglomerular feedback (TGF) response to increased distal delivery. However, a muted TGF response would contradict the notion of remnant kidney as a prototype of angiotensin II (ANG II) excess, since ANG II normally sensitizes the TGF response and stimulates proximal reabsorption. We examined the role of ANG II as a modulator of TGF and proximal reabsorption in 7 days after STN in male rats. Single-nephron glomerular filtration rate (SNGFR) and proximal reabsorption ([J.sub.prox]) were measured in late proximal collections while perfusing Henle's loop for minimal and maximal TGF stimulation in rats treated with the angiotensin type 1 ([AT.sub.1]) receptor blocker losartan or placebo in drinking water for 7 days. Perfusion of Henle's loop yielded a robust TGF response in sham-operated rats. In STN, the feedback responses were highly variable and nil, on average. Paradoxical TGF responses to augmented late proximal flow were confirmed in SNGFR measurements from the early distal nephron. Chronic losartan treatment normalized the average TGF response without reducing the variability. [J.sub.prox] was subtly affected by chronic losartan in sham surgery or STN, after controlling for differences in SNGFR. However, when administered acutely into the early S1 segment, losartan potently suppressed [J.sub.prox] in STN and sham-operated rats alike. Chronic losartan stabilizes the TGF system in remnant kidneys. This cannot be explained by currently known actions of [AT.sub.1] receptors but is commensurate with a salutary effect of an intact TGF system on dynamic autoregulation of intraglomerular flow and pressure. proximal tubular reabsorption; glomerulotubular balance; hyperfiltration

N-methyl-D-aspartate receptors (NMDA) are expressed in the kidney, where little is known of their functional role. Several series of micropuncture experiments were performed in hydropenic rats using the NMDA channel blocker, MK801, and the NMDA coagonist, L-glycine, to probe NMDA for effects on single-nephron glomerular filtration rate (SNGFR) and proximal reabsorption ([J.sub.prox]). During intravenous infusion of MK801 or L-glycine, Henle's loop was perfused to manipulate SNGFR via tubuloglomerular feedback (TGF), thereby facilitating analysis of glomerulotubular balance. To confirm local actions on the kidney, MK801 was delivered to the glomerulus by microperfusion past the macula densa and to the proximal tubule by microperfusion into the early S1 segment. By all measures, MK801 acted on the glomerulus to reduce SNGFR, and acted on the proximal tubule to suppress [J.sub.prox], while having no effect on the responsiveness of TGF. L-Glycine raised SNGFR, dampened the TGF response, and could not be proved to independently stimulate proximal reabsorption. NMDA exerts a tonic vasodilatory influence on the glomerulus and a proreabsorptive effect on the proximal tubule. These combined effects allow NMDA to modulate SNGFR with minimal impact on late proximal flow. The full effects of L-glycine infusion on proximal tubule and TGF response do not extrapolate from the response to NMDA blockade. N-methyl-D-aspartate receptors; L-glycine; tubuloglomerular feedback; glomerulotubular balance; micropuncture

Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg x [kg.sup.-1] x [day.sup.-1]), or placebo. Single nepbron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption ([J.sub.prox]) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed [J.sub.prox] independent of SNGFR. Suppression of [J.sub.prox] was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes. diabetic hyperfiltration; proximal tubular reabsorption; tubuloglomerular feedback; glomerulotubular balance

Infusion of L-arginine produces an increase in glomerular filtration via kidney vasodilation, correlating with increased kidney excretion of nitric oxide (NO) metabolites, but the specific underlying mechanisms are unknown. We utilized clearance and micropuncture techniques to examine the whole kidney glomerular filtration rate (GFR) and single nephron GFR (SNGFR) responses to 1) L-arginine (ARG), 2) ARG+octreotide (OCT) to block insulin release, 3) ARG+OCT+insulin (INS) infusion to duplicate ARG-induced insulin levels, and 4) losartan (LOS), an angiotensin AT-1 receptor blocker, +ARG+OCT. ARG infusion increased GFR, while increasing insulin levels. OCT coinfusion prevented this increase in GFR, but with insulin infusion to duplicate ARG induced rise in insulin, the GFR response was restored. Identical insulin levels in the absence of ARG had no effect on GFR. In contrast to ARG infusion alone, coinfusion of OCT with ARG reduced proximal tubular fractional and absolute reabsorption potentially activating tubuloglomerular feedback. Losartan infusion, in addition to ARG and OCT (LOS+ARG+OCT), restored the increase in both SNGFR and proximal tubular reabsorption, without increasing insulin levels. In conclusion, 1) hyperfiltration responses to ARG require the concurrent, modest, permissive increase in insulin; 2) inhibition of insulin release after ARG reduces proximal reabsorption and prevents the hyperfiltration response; and 3) inhibition of ANG II activity restores the hyperfiltration response, maintains parallel increases in proximal reabsorption, and overrides the arginine/octreotide actions. nitric oxide; glomerular filtration rate; octreotide

The tubuloglomerular feedback (TGF) system serves to establish an appropriate balance between tubular reabsorption and glomerular filtration rate (GFR). High salt at the macnia densa activates TGF to decrease GFR. Effector molecules for the TGF signal include ATP and adenosine. Over time, the GFR will adapt by increasing even if a high salt concentration persists. A potential modulator of this TGF adaptation is nitric oxide synthase-1-derived nitric oxide (NO). In isolated glomerular preparations, we developed a system for evaluating the effects of changing dietary salt on ecto-5'-nucleotidase (ecto-5'-NT) activity, the final enzyme in the conversion of ATP to adenosine. We found observable ecto-5'-NT activity in isolated glomeruli and that this activity can be regulated by dietary salt, with high salt increasing activity. Conversely, NO decreases ecto-5'-NT activity in glomerular preparations. Moreover, NO inhibition of ecto-5'-NT activity is suppressed in the presence of dithiothreitol, suggesting nitrosylation as a reversible, oxidative stress-sensitive mechanism. The salt-induced activation of ecto-5'-NT correlates with high salt resetting of TGF. NO inhibition of enzymatic activity could be part of the adaptive phase. adenosine; glomerular filtration rate

Oxygen consumed by the kidney (Q[o.sub.2]) is primarily obligated to sodium reabsorption ([T.sub.Na]). The relationship of Q[o.sub.2] to [T.sub.Na] (Q[o.sub.2]/[T.sub.Na]) may be altered by hormones and autacoids. To examine whether Q[o.sub.2]/[T.sub.Na] depends on the mechanism of sodium reabsorption, we first evaluated the effects on Q[o.sub.2] and Q[o.sub.2]/[T.sub.Na] of benzolamide (BNZ), a proximal diuretic that works by inhibiting membrane carbonic anhydrase. During BNZ infusion in anesthetized rats, Q[o.sub.2] increased by 50% despite a 25% decline in [T.sub.Na]. However, BNZ failed to increase Q[o.sub.2]/[T.sub.Na] when given along with the adenosine A1 receptor blocker, DPCPX, which inhibits basolateral Na-bicarbonate cotransport (NBC1), or EIPA, which inhibits sodium-hydrogen exchange (NHE). Incubating freshly harvested rat proximal tubules with BNZ also caused Q[o.sub.2] to increase by 62%, an effect that was prevented by blocking the apical NHE3 with S3226. Blocking NBC1 or NHE3 in the proximal tubule will have opposite effects on cell pH, but both maneuvers should reduce active chloride transport. In conclusion, inhibiting membrane carbonic anhydrase in the proximal tubule increases [Qo.sub.2] and reduces the energy efficiency of sodium reabsorption by the kidney. This is not purely due to shifting the burden of reabsorption to a more expensive site downstream from the proximal tubule. Instead, increased cost may be incurred within the proximal tubule as the result of increased active chloride transport. NaCl reabsorption; transport efficiency; proximal tubule; benzolamide; adenosine; sodium-hydrogen exchange

Lipopolysaccharide (LPS) is used experimentally to elicit the innate physiological responses observed in human sepsis. We have previously shown that LPS causes depletion of plasma arginine before inducible nitric oxide synthase (iNOS) activity, indicating that changes in arginine uptake and/or production rather than enhanced consumption are responsible. Because the kidney is the primary source of circulating arginine and renal failure is a hallmark of septicemia, we determined the time course of changes in arginine metabolism and kidney function relative to iNOS expression. LPS given intravenously to anesthetized rats caused a decrease in mean arterial blood pressure after 120 min that coincided with increased plasma nitric oxide end products (NOx) and iNOS expression in lung and liver. Interestingly, impairment of renal function preceded iNOS activity by 30-60 min and occurred in tandem with decreased renal arginine production. The baseline rate of renal arginine production was ~60 [micro]mol * [h.sup.-1] * [kg.sup.-1], corresponding to an apparent plasma half-life of ~20 min, and decreased by one-half within 60 min of LPS. Calculations based on the systemic production and clearance show that normally only 5% of kidney arginine output is destined to become nitric oxide and that inducible nitric oxide synthase; sepsis; lipopolysaccharide; ornithine

Protein intake regulates the vasodilatory function of the kidney and NMDA receptor expression. Am J Physiol Regul Integr Comp Physiol 287: R1184-R1189, 2004. First published July 8, 2004; doi: 10.1152/ajpregu.00169.2003.--Glycine infusion in normal rats causes an increase in renal plasma flow and glomerular filtration rate (GFR). Although the renal response to glycine infusion is well characterized, the mechanism initiating this vasodilation is unknown. We recently observed functionally active N-methyl-D-aspartate (NMDA) receptors in the kidney, located primarily in tubular structures. The mechanisms regulating activity of the NMDA receptor within the kidney are also unknown, as is its normal day-to-day functional role. Therefore, we hypothesize that dietary protein may impact the functional response to glycine infusion in both untreated rats and rats pretreated with angiotensin-converting enzyme (ACE) inhibitor and, furthermore, that renal NMDA receptors may be involved in the glycine response. Surprisingly, 2 wk of low-protein diet (8% protein vs. 21% protein in control diet) totally inhibited the glycine-induced vasodilation and GFR response. Associated with the absence of renal vasodilation, a significant reduction in proximal tubular reabsorption was observed during glycine infusion in low-protein-diet rats. In contrast to the disease models previously studied in our laboratory, administration of ACE inhibitors did not restore the glycine response in rats treated with low-protein diet. Western blots of normal- and low-protein-diet kidneys demonstrate that the newly described renal NMDA receptor is downregulated in rats fed a low-protein diet. Low-protein feeding results in loss of glycine-induced vasodilation and GFR responses associated with decreased renal NMDA receptor expression. Kidney NMDA receptor expression is conditioned by protein intake, and this receptor may play an important role in the kidney vasodilatory response to glycine infusion and protein feeding in rats. glycine; N-methyl-D-aspartate receptor; renal hemodynamics; dietary protein

Early diabetes as a model for testing the regulation of juxtaglomerular NOS I. Am J Physiol Renal Physiol 287: F732-F738, 2004. First published June 22, 2004; 10.1152/ajprenal.00340.2003.--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. glomerular filtration; macula densa; micropuncture; nitric oxide; tubuloglomerular feedback

At the onset of diabetes mellitus, the glomerular filtration rate becomes supranormal. Discovery science has identified many abnormalities in the early diabetic kidney that apparently contribute to this phenotype. A serviceable understanding of the early diabetic kidney requires this information to fit together. It is the purpose of this article to present an archetype that explains multiple nuances of kidney function in early diabetes. We refer to this archetype as the 'tubular hypothesis of glomerular filtration.'' Its basic tenet is that strange effects of diabetes on glomerular filtration stem from primary effects on the proximal tubule or loop of Henle that impact glomerular filtration by feedback through the macula densa. This theory can explain diabetic hyperfiltration, a paradoxical effect of dietary salt on glomerular filtration rate in diabetes, and the renal response to dietary protein and amino acid infusion in diabetes. The discussion centers on the kidney as an integrated system of parts rather than on the specific cellular mechanisms that comprise those parts. tubuloglomerular feedback; glomerulotubular balance; juxtaglomerular apparatus

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 re. absorption dominates. In low-protein diabetes, the vascular effect is enhanced and overrides the effect of reduced tubular reabsorption. glomerular filtration; tubuloglomerular feedback; tubular reabsorption; loop of Henle; streptozotocin

Tubuloglomerular feedback activation and proximal reabsorption reduction are achieved through renal carbonic anhydrase inhibition. Tubuloglomerular feedback testing by micropuncture and videometric flow veocitometry shows resetting in free-flowing nephrons in euvolemic rats during carbionic anhydrase inhibitor benzolamide systemic infusion. Results show that decreased proximal reabsorption causes tubuloglomerular feedback rightward resetting.

The hypothesis that sustained changes in the late proximal flow of glomerular filtration can cause resetting of tubuloglomerular feedback (TGF) function was tested using Inactin-anesthetized euvolemic rats. Changes in the fractional compensation (C) of TGF were observed. Resetting of TGF function was confirmed when C recovered 70% of its original value following suppression. It was shown that a sustained increase in late proximal flow can induce TGF resetting.

The rates of glomerular filtration and proximal tubular reabsorption are decreased when the functions of endothelium-dependent nitric oxide (EDNO) are restrained by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). Injection of L-NMMA caused a reduction in the single-nephron glomerular filtration rate in control and sham surgery animals but not in rats that underwent ipsilateral surgical renal denervation (DNX). Similar observations are noticed for proximal reabsorption which is restricted by prior DNX. Therefore, the glomerular and tubular effects by nitric oxide synthase blockades require some part of renal adrenergic activity.