Tonic basal release of nitric oxide (NO) by vascular endothelial cells controls blood pressure (BP) in the basal state. In these studies we investigated the effects of chronic inhibition of basal NO synthesis in the rat for a 2-mo period. Significant systemic hypertension developed in chronically NO-blocked rats compared to controls. Marked renal vasoconstriction was also observed with elevations in glomerular blood pressure (PGC) and reductions in the glomerular capillary ultrafiltration coefficient (Kf). Chronically NO-blocked rats also develop proteinuria and glomerular sclerotic injury compared to controls. These studies therefore describe a new model of systemic hypertension with glomerular capillary hypertension and renal disease due to chronic blockade of endogenous NO synthesis. These observations highlight the importance of the endogenous NO system in control of normal vascular tone and suggest that hypertensive states may result from relative NO deficiency. (J. Clin. Invest. 1992. 90:278-281.) Key words: nitric oxide * hypertension glomerulus * single nephron glomerular filtration rate

IntroductionAt the onset of diabetes mellitus, the kidney begins to grow and GFR increases. Some time later, structural changes can occur in the glomerulus which form the basis for progressive diabetic nephropathy. Intrarenal hemodynamic abnormalities, as manifest by glomerular hyperfiltration, are thought to be among the foremost factors responsible for the onset and progression of diabetic glomerulopathy. To account for these hemodynamic abnormalities, investigators have characterized the functional effects of diabetes on the various segments of the glomerular microvasculature (reviewed in ref. 1), and many substances have been invoked as humoral mediators of vasodilation in the diabetic glomerulus (reviewed in ref.2). However, no single cause has emerged to account for glomerular hyperfiltration in diabetes. The principal idea behind the present study is that glomerular hyperfiltration in diabetes does not develop mainly because of disordered microvascular function or from imbalanced hormones impinging directly on the glomerulus. Instead, we propose that glomerular hyperfiltration results mainly from a primary increase in proximal tubular reabsorption which causes GFR to increase through the physiologic actions of tubuloglomerular feedback (TGF). Furthermore, we propose that this primary increase in reabsorption results, in good part, from hypertrophy of the tubule. This "tubular hypothesis" of diabetic hyperfiltration reverses the order of events as typically envisioned for the diabetic kidney, in which a primary reduction in vascular resistance causes GFR to increase and the tubule then grows larger in order to accommodate the increased filtered load.If the TGF response were slow enough, one could confirm the tubular hypothesis of glomerular hyperfiltration by recording a lag time between enlargement of the kidney and the onset of hyperfiltration. However, the time required for TGF to evoke a change in GFR is on the order of several seconds (3), whereas diabetic hypertrophy proceeds continuously over days. Therefore, a TGF-mediated cause and effect relationship between kidney size and GFR will not be revealed by their temporal relationship. In fact, the most that can be said of the temporal relationship between hyperfiltration and renal hypertrophy in human type I diabetes is that they both occur early (4). Similarly, in rats with diabetes induced by streptozotocin, kidney size (5), kidney protein/DNA ratio (6), and GFR all increase within 24 hours of the onset of diabetes, the latter notwith- In early diabetes, the kidney grows and the glomerular filtration rate (GFR) increases. This growth is linked to ornithine decarboxylase (ODC). The study of hyperfiltration has focused on microvascular abnormalities, but hyperfiltration may actually result from a prior increase in capacity for proximal reabsorption which reduces the signal for tubuloglomerular feedback (TGF). Experiments were performed in Wistar rats after 1 week of streptozotocin diabetes. Kidney weight, ODC activity, and GFR were correlated in diabe...

Magnetotactic bacteria (MTB) of the genus 'Candidatus Magnetobacterium' in phylum Nitrospirae are of great interest because of the formation of hundreds of bullet-shaped magnetite magnetosomes in multiple bundles of chains per cell. These bacteria are worldwide distributed in aquatic environments and have important roles in the biogeochemical cycles of iron and sulfur. However, except for a few short genomic fragments, no genome data are available for this ecologically important genus, and little is known about their metabolic capacity owing to the lack of pure cultures. Here we report the first draft genome sequence of 3.42 Mb from an uncultivated strain tentatively named 'Ca. Magnetobacterium casensis' isolated from Lake Miyun, China. The genome sequence indicates an autotrophic lifestyle using the Wood-Ljungdahl pathway for CO 2 fixation, which has not been described in any previously known MTB or Nitrospirae organisms. Pathways involved in the denitrification, sulfur oxidation and sulfate reduction have been predicted, indicating its considerable capacity for adaptation to variable geochemical conditions and roles in local biogeochemical cycles. Moreover, we have identified a complete magnetosome gene island containing mam, mad and a set of novel genes (named as man genes) putatively responsible for the formation of bullet-shaped magnetite magnetosomes and the arrangement of multiple magnetosome chains. This first comprehensive genomic analysis sheds light on the physiology, ecology and biomineralization of the poorly understood 'Ca. Magnetobacterium' genus.

Nephron function is stabilized by tubuloglomerular feedback (TGF). TGF operates within the juxtaglomerular apparatus, sensing changes in tubular flow and eliciting compensatory changes in single nephron GFR (SNGFR). The mediator(s) of TGF remains unconfirmed. One theory is that ATP consumed in active transport by the macula densa leads to formation of adenosine, which causes glomerular vasoconstriction. We performed micropuncture in rats to test this hypothesis. Adenosine activity was manipulated by microperfusing nephrons with adenosine A1 receptor blocker, A1-agonist, or 5'-nucleotidase inhibitor. Effects on TGF were characterized by changes in TGF efficiency (the compensation for small perturbations in tubular flow) and by changes in the maximum range over which TGF can cause SNGFR to change. These data were further applied to generate TGF profiles [SNGFR versus late proximal flow (V(LP))]. TGF efficiency was significantly reduced by blocking A1-receptors. TGF efficiency, TGF range, and the slope of the TGF profile (DeltaSNGFR/DeltaV(LP)) were all significantly reduced by blocking 5'-nucleotidase. When adenosine activity was clamped by combining 5'-nucleotidase inhibitor with A1-agonist to determine whether TGF requires adenosine to be present or to fluctuate, the TGF slope was reduced by 83%, indicating that adenosine activity must fluctuate for normal TGF to occur and that adenosine is a mediator of TGF.