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Kidney blood flow is highly regulated by a combination of myogenic autoregulation, multiple neurohormonal systems and the tubuloglomerular feedback system, the later of which specifically relates tubular reabsorption to the filtered load. Oxygen and substrate requirements of the kidney are dictated by both supply of oxygen and substrates and metabolic demands of the kidney. The tubuloglomerular feedback system utilizes mediators which are intimately linked to cellular metabolism, ATP and adenosine. This system based upon communication transfer between the macular densa and the afferent arteriole stabilizes kidney function and is not static but temporally adapts or resets to new external physiologic conditions. Such temporal adaptation occurs via modulators such as nitric oxide (NO), primarily derived from NOS-1, angiotensin II and COX-2 products. These hormonal influences also exert capacities to modulate cellular demands for oxygen, particularly NO which decreases oxygen consumption via multiple mechanisms. The several mechanisms whereby NO and other hormonal systems and transporter activity can regulate and produce changes in kidney metabolic demands are discussed. Modulators which influence temporal adaptation and resetting of TGF are also significant contributors to the regulation of cellular oxygen consumption in the kidney. These systems may act in concert to preserve the coordination of filtered load and tubular reabsorption and the metabolic demands of kidney function, thereby determining the ischemic threshold for kidney function.

Using micropuncture techniques in euvolemic adult male Munich-Wistar rats, we assessed the functional role of renal β-adrenoceptors in mediating neural control of glomerular filtration and proximal tubular reabsorption. The determinants of nephron filtration and rate of proximal tubular reabsorption were measured in two groups of animals before and after acute surgical renal denervation (DNX). Group A animals (n = 6) were pretreated with the β-adrenoceptor antagonist proprmolol (25 mg/kg body weight per day for 4–6 days). Group B animals (n = 7) served as non–β-blocked controls. Acute renal DNX resulted in no significant change in nephron filtration rate or any of its determinants in either group. Acute DNX caused similar decrements in the rate of fluid reahsorption from the proximal convoluted tubule of β-blocked and control rats. Loop of Henle fluid reahsorption did not appear to he affected by DNX in either group. Because the effect of denervation on proximal tubular reabsorption was not conditioned by prior β-blockade, the β-adrenoceptors present within the proximal convoluted tubule do not appear to he the primary mediators of the adrenergic influence on fluid transport in that segment of the nephron.

Polyamines are required for entry and progression of the cell cycle. As such, augmentation of polyamine levels is essential for cellular transformation. Polyamines are autoregulated through induction of antizyme, which represses both the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase and cellular polyamine transport. In the present study we demonstrate that agmatine, a metabolite of arginine via arginine decarboxylase (an arginine pathway distinct from that of the classical polyamines), also serves the dual regulatory functions of suppressing polyamine biosynthesis and cellular polyamine uptake through induction of antizyme. The capacity of agmatine to induce antizyme is demonstrated by: (a) an agmatine-dependent translational frameshift of antizyme mRNA to produce a full-length protein and (b) suppression of agmatine-dependent inhibitory activity by either anti-antizyme IgG or antizyme inhibitor. Furthermore, agmatine administration depletes intracellular polyamine levels to suppress cellular proliferation in a transformed cell line. This suppression is reversible with polyamine supplementation. We propose a novel regulatory pathway in which agmatine acts as an antiproliferative molecule and potential tumor suppressor by restricting the cellular polyamine supply required to support growth.

Zusammenfassung Neuere Befunde werden dargelegt, die zeigen, daß die glomeruläre Filtrationsrate exakt reguliert wird und nicht nur die passive Folge von unkontrollierten renalen und nicht-renalen Faktoren ist. Änderungen des renalen Plasmaflusses und, untergewissen Bedingungen, Änderungen des glomerulären Permeabilitätskoeffizienten sind die hauptsächlich bestimmenden Faktoren, die die glomeruläre Filtrationsrate beeinflussen. Aufgrund von neueren Untersuchungen kann man annehmen, daß eine größere Anzahl von Hormonen nach intravenöser Verabreichung in der Lage ist, die glomeruläre Filtrationsrate zu beeinflussen. Dieser Effekt wird durch eine Änderung des renalen Plasmaflusses bzw. durch eine Abnahme des glomerulären Permeabilitätskoeffizienten bedingt. Bei der durch Hormone ausgelösten Veränderung des glomerulären Permeabilitätskoeffizienten scheint Angiotensin II eine entscheidende Vermittlerrolle als „final common pathway“ zu spielen. Von den untersuchten hormonellen Substanzen hat offensichtlich nur ADH einen angiotensin-unabhängigen Effekt. Weiter konnte gezeigt werden, daß unter normalen und veränderten physiologischen Bedingungen Hormone, hier besonders Angiotensin II, an der aktiven Regulation der glomerulären Filtrationsrate beteiligt sind. Dieser Effekt erfolgt über eine Beeinflussung des glomerulären Permeabilitätskoeffizienten und damit über eine Änderung des renalen Plasmaflusses.

Arginine decarboxylase is present in the kidney and metabolizes the amino acid, arginine, to agmatine. Agmatine increases filtration rate in single nephrons (J. J. Lortie, W. F. Novotny, O. W. Peterson, V. Vallon, K. Malvey, M. Mendonca, J. Satriano, P. Insel, S. C. Thomson, and R. C. Blantz. J. Clin. Invest. 97:413-420, 1996). Experiments were conducted to determine whether exogenously administered agmatine exerts these effects via interaction with nitric oxide synthase (NOS) and whether this interaction depends upon alpha 2-adrenergic receptors. Agmatine microperfused (1 microM) into the urinary space of surface glomeruli of the rat increased nephron filtration rate from 33 +/- 4 to 40 +/- 5 nl/min with complete recovery within 10 min. When NG-monomethyl-L-arginine (L-NMMA), a nonselective NOS inhibitor, was systemically infused, agmatine no longer increased single-nephron glomerular filtration rate (SNGFR). BHT-933, an alpha 2-adrenergic agonist, did not increase SNGFR and was unaffected by concurrent L-NMMA. In vitro incubation of freshly harvested glomeruli with agmatine resulted in significant increases in the generation of cGMP, effects similar to carbachol, and blocked by nitro-L-arginine methyl ester (L-NAME) but not yohimbine, an alpha 2-adrenergic antagonist. Agmatine exerts effects on glomerular ultrafiltration via a constitutive NOS-dependent mechanism, and this does not require the participation of alpha 2-adrenoreceptors.