Nitric oxide mediates anomalous tubuloglomerular feedback in rats fed high-NaCl diet after subtotal nephrectomy

Tubuloglomerular feedback (TGF) responses become anomalous in rats fed high-NaCl diet after subtotal nephrectomy (STN), such that stimulating TGF causes single nephron GFR (SNGFR) to increase rather than decrease. Micropuncture experiments were performed to determine whether this anomaly results from heightened nitric oxide response to distal delivery, which is a known mechanism for resetting TGF, or from connecting tubule TGF (cTGF), which is a novel amiloride-inhibitable system for offsetting TGF responses. Micropuncture was done in Wistar Froemter rats fed high-NaCl diet (HS) for 8–10 days after STN or sham nephrectomy. TGF was manipulated by orthograde microperfusion of Henle’s loop with artificial tubular fluid with or without NOS inhibitor, LNMMA, or the cell-impermeant amiloride analog, benzamil. SNGFR was measured by inulin clearance in tubular fluid collections from the late proximal tubule. TGF responses were quantified as the increase in SNGFR that occurred when the perfusion rate was reduced from 50 to 8 nl/min in STN or 40 to 8 nl/min in sham animals. The baseline TGF response was anomalous in STN HS (−4 ± 3 vs 14 ± 3 nl/min, P < 0.001). TGF response was normalized by perfusing STN nephron with LNMMA (14 ± 3 nl/min, P < 0.005 for ANOVA cross term) but not with benzamil (−3 ± 4 nl/min, P = 0.4 for ANOVA cross term). Anomalous TGF occurs in STN HS due to heightened effect of tubular flow on nitric oxide signaling, which increases to the point of overriding the normal TGF response. There is no role for cTGF in this phenomenon.

Alternative Detachment Technique for Electrically Detachable Coils: Rescue From an Unintended Complication

BACKGROUND Embolization of intracranial aneurysms with the use of detachable coils has become the most widely used therapy for this condition. However, unexpected device failure can lead to critical complications. OBJECTIVE To describe an alternative detachment technique for various electrically detachable coils (eg, Target of Stryker Neurovascular, Presidio and Microphere of Codman Neurovascular, and MicroPlex and Hydrocoil of MicroVention Terumo) that can be used when standard troubleshooting techniques are not effective and the physician is not able to remove a coil. METHODS The alternative detachment method involved the restoration of the current pathway with the use of an alligator clip wire and the distal end of a new coil delivery wire of the same type. The detachment mechanism used in this method is the same as that normally used for each system. RESULTS We found that this alternative maneuver was both feasible and reproducible. Moreover, an electrically detachable coil was successfully detached with the use of this method, especially when detachment failure was the result of distal delivery wire and connector damage. No additional complications were noted. CONCLUSION An alternative detachment technique involving the reconstruction of the electric circuit could be a safe method of rescue in the potentially risky situation caused by detachment failure during embolization of cerebral aneurysms with electrically detachable coils.

A mathematical model of the rat nephron: glucose transport

Mathematical models of the proximal tubule (PT), loop of Henle (LOH), and distal nephron have been combined to simulate transport by rat renal tubules. The ensemble is composed of 24,000 superficial (SF) nephrons and 12,000 juxtamedullary (JM) nephrons in 5 classes (according to LOH length); all coalesce into 7,200 connecting tubules (CNT). Medullary interstitial solute concentrations are specified. The model equations require that each nephron glomerular filtration rate (GFR) satisfies a tubuloglomerular feedback (TGF) relationship, and each initial hydrostatic pressure yields a common CNT pressure; that common CNT pressure is determined from an overall distal hydraulic resistance to flow. By virtue of the greater GFR for JM nephrons, fluid delivery to SF and JM tubules is comparable. Glucose reabsorption is restricted to the PT, cotransported with one Na in the convoluted tubule (SGLT2), and two Na in the straight tubule (SGLT1). Increasing ambient glucose from 5 to 10 mM increases proximal Na reabsorption and decreases distal delivery. This is mitigated by a TGF-mediated increase in GFR, and may thus be an etiology for TGF-mediated glomerular hyperfiltration. With SGLT2 inhibition by 95%, the model predicts that under normoglycemic conditions about 60% of filtered glucose will still be reabsorbed, so that profound glycosuria is not to be expected. Compared with glucose-driven osmotic diuresis, SGLT2 inhibition provokes greater natriuresis. When hyperglycemia is superimposed on SGLT2 inhibition, the model suggests that natriuresis may be severe, reflecting synergy of a proximal diuretic and osmotic diuresis. In sum, the model captures TGF-mediated diabetic hyperfiltration and predicts glomerular protection with SGLT2 inhibition.

Salt sensitivity of tubuloglomerular feedback in the early remnant kidney

We previously reported internephron heterogeneity in the tubuloglomerular feedback (TGF) response 1 wk after subtotal nephrectomy (STN), with 50% of STN nephrons exhibiting anomalous TGF (Singh P, Deng A, Blantz RC, Thomson SC. Am J Physiol Renal Physiol 296: F1158–F1165, 2009). Presently, we tested the theory that anomalous TGF is an adaptation of the STN kidney to facilitate increased distal delivery when NaCl balance forces the per-nephron NaCl excretion to high levels. To this end, the effect of dietary NaCl on the TGF response was tested by micropuncture in STN and sham-operated Wistar rats. An NaCl-deficient (LS) or high-salt NaCl diet (HS; 1% NaCl in drinking water) was started on day 0 after STN or sham surgery. Micropuncture followed 8 days later with measurements of single-nephron GFR (SNGFR), proximal reabsorption, and tubular stop-flow pressure (PSF) obtained at both extremes of TGF activation, while TGF was manipulated by microperfusing Henle's loop (LOH) from the late proximal tubule. Activating TGF caused SNGFR to decline by similar amounts in Sham-LS, Sham-HS and STN-LS [ΔSNGFR (nl/min) = −16 ± 2, −11 ± 3, −11 ± 2; P = not significant by Tukey]. Activating TGF in STN-HS actually increased SNGFR by 5 ± 2 nl/min ( P < 0.0005 vs. each other group by Tukey). HS had no effect on the PSF response to LOH perfusion in sham [ΔPSF (mmHg) = −9.6 ± 1.1 vs. −9.8 ± 1.0] but eliminated the PSF response in STN (+0.3 ± 0.9 vs. −5.7 ± 1.0, P = 0.0002). An HS diet leads to anomalous TGF in the early remnant kidney, which facilitates NaCl and fluid delivery to the distal nephron.

Unexpected effect of angiotensin AT1 receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy

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 ( Jprox) 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 (AT1) 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. Jprox 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 Jprox 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 AT1 receptors but is commensurate with a salutary effect of an intact TGF system on dynamic autoregulation of intraglomerular flow and pressure.

Maternal renal insufficiency alters plasma composition and renal function in the fetal sheep

To determine the effects of chronic maternal renal insufficiency on fetal renal function, we studied nine fetuses whose mothers underwent subtotal nephrectomy at least 2 mo before mating (STNxF) and seven fetuses from intact ewes (IntF) (126–128 days of gestation, term 150 days). STNxF had lower hematocrit ( P < 0.05), plasma chloride ( P < 0.01), and creatinine levels ( P < 0.01), and the length-to-width ratio of their kidneys was reduced ( P < 0.05). They excreted twice as much urine ( P < 0.05) and sodium ( P < 0.01). Total ( P = 0.01) and proximal fractional sodium reabsorptions ( P < 0.05) were lower in STNxF; distal delivery of sodium ( P < 0.05) and distal fractional sodium reabsorption ( P < 0.05) were higher. They tended to have suppressed renin levels ( P = 0.06). Infusions of amino acids (alanine, glycine, proline, and serine at 0.32 mmol/min for 1 h and 0.64 mmol/min for 2 h intravenously), known to stimulate renal blood flow and glomerular filtration rate in fetal sheep, did so in IntF ( P < 0.01). Arterial pressure also increased ( P < 0.01). These effects were not observed in STNxF. In summary, chronic maternal renal insufficiency was associated with profound alterations in fetal renal excretion of fluid and electrolytes and impaired renal hemodynamic and glomerular responses to amino acid infusion. Whether these marked changes in the renal function of fetuses carried by STNx ewes are associated with alterations in renal function in postnatal or adult life remains to be determined.

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature.

Neuronal NOS contributes to biphasic autoregulatory response during enhanced TGF activity

To assess the afferent arteriolar autoregulatory response during increased activity of the tubuloglomerular feedback (TGF) mechanism and to delineate the contribution of neuronal nitric oxide synthase (nNOS) to this response, afferent arteriolar diameter responses to changes in renal perfusion pressure (RPP) were monitored in vitro using the blood-perfused rat juxtamedullary nephron preparation. At RPP of 100 mmHg, basal afferent arteriolar diameter averaged 21.1 ± 1.4 μm ( n = 9). The initial and sustained constrictor responses of afferent arterioles to a 60-mmHg increase in RPP averaged 14.8 ± 1.4% and 13.3 ± 1.3%, respectively. Acetazolamide treatment, which enhances TGF responsiveness by increasing distal nephron volume delivery, significantly decreased basal afferent arteriolar diameter by 8.2 ± 0.5% and enhanced the initial response (25.5 ± 2.3%) to a 60-mmHg increase in RPP but did not alter the sustained response (14.3 ± 1.5%). In another series of experiments, nNOS inhibition with 10 μM S-methyl-l-thiocitrulline (l-SMTC) significantly decreased afferent arteriolar diameter from 20.3 ± 1.3 to 18.3 ± 1.1 μm ( n = 7) and enhanced both the initial (34.4 ± 3.5%) and sustained constrictor responses (27.6 ± 2.9%) to a 60-mmHg increase in RPP. Treatment with acetazolamide further enhanced both initial (56.4 ± 3.0%) and sustained responses (54.6 ± 2.7%). Interruption of distal delivery by transection of the loops of Henle prevented the enhanced responses to increases in RPP elicited with either acetazolamide orl-SMTC. These results indicate that nNOS contributes to the counteracting resetting process of biphasic afferent arteriolar constrictor responses to increases in RPP through a TGF-dependent mechanism.