There has been an explosive growth of interest in the multiple interacting paracrine systems that influence renal microvascular function. This review first discusses the membrane activation mechanisms for renal vascular control. Evidence is provided that there are differential activating mechanisms regulating pre- and postglomerular arteriolar vascular smooth muscle cells. The next section deals with the critical role of the endothelium in the control of renal vascular function and covers the recent findings related to the role of nitric oxide and other endothelial-derived factors. This section is followed by an analysis of the roles of vasoactive paracrine systems that have their origin from adjoining tubular structures. The interplay of signals between the epithelial cells and the vascular network to provide feedback regulation of renal hemodynamics is developed. Because of their well-recognized contributions to the regulation of renal microvascular function, three major paracrine systems are discussed in separate sections. Recent findings related to the role of intrarenally formed angiotensin II and the prominence of the AT1 receptors are described. The possible contribution of purinergic compounds is then discussed. Recognition of the emerging role of extracellular ATP operating via P2 receptors as well as the more recognized functions of the P1 receptors provides fertile ground for further studies. In the next section, the family of vasoactive arachidonic acid metabolites is described. Possibilities for a myriad of interacting functions operating both directly on vascular smooth muscle cells and indirectly via influences on endothelial and epithelial cells are discussed. Particular attention is given to the more recent developments related to hemodynamic actions of the cytochrome P-450 metabolites. The final section discusses unique mechanisms that may be responsible for differential regulation of medullary blood flow by locally formed paracrine agents. Several sections provide perspectives on the complex interactions among the multiple mechanisms responsible for paracrine regulation of the renal microcirculation. This plurality of regulatory interactions highlights the need for experimental strategies that include integrative approaches that allow manifestation of indirect as well as direct influences of these paracrine systems on renal microvascular function.

Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increase intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectable increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II-infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.

The present study examined whether preglomerular arterioles of the rat produce 20-hydroxyeicosatetraenoic acid (20-HETE) and whether 20-HETE is vasoactive on these vessels. Raf preglomerular arterioles produced 20-HETE (4.8 +/- 1.0 pmol.min-1.mg-1, n = 7) and, to a lesser extent, 14-, 15-, 11-, and 12-dihydroxyeicosatetraenoic acid, 6-ketoprostaglandin F/alpha and prostaglandin E2 when incubated with [14C]larachidonic acid. The results of immunoblotting and reverse-transcription polymerase chain reaction experiments indicate that these vessels express mRNA and protein for a P-450 4A2 enzyme. With the use of a rat juxtamedullary nephron microvascular preparation perfused in vitro with a cell-free media, addition of 20-HETE (1 nM-1 microM) to the bath reduced the diameter of proximal and distal portions of the efferent arterioles. At a concentration of 1 microM, the diameter of the proximal and distal portions of the afferent arteriole fell by 14 +/- 1 and 16 +/- 3% after 20-HETE. The response to 20-HETE (1 microM) was not altered by blockade of cyclooxygenase, lipoxygenase, and p-450 pathways. Blockade of the large-conductance Ca(2+)-activated K+ channel with tetraethylammonium (1 mM) reduced the diameter of afferent arterioles by 10% and blocked the vasoconstrictor response to 20-HETE (1 microM). These results indicate that 20-HETE is an endogenous constrictor of preglomerular arterioles and suggest a role for the P-450 4A2 enzyme in the regulation of renal vascular tone.

Abstract-The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10Ϯ2 ng/mL in normal-salt angiotensin hypertension and 19Ϯ3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161Ϯ4 mm Hg in normal-salt and 172Ϯ5 mm Hg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140Ϯ5 mm Hg in the normal-salt angiotensin hypertension group and to 151Ϯ6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension. Key Words: kidney Ⅲ inflammation Ⅲ endothelium-derived factors Ⅲ albuminuria A lthough treatment of hypertension has significantly advanced in recent decades, a chronic elevation in blood pressure still results in progressive renal damage, as evidenced by the escalating incidence of end-stage renal disease (ESRD). 1,2 The development of hypertension after long-term administration of angiotensin has many of the same renal and vascular changes that are associated with human essential hypertension. 3,4 Likewise, animal models of angiotensindependent hypertension demonstrate a further elevation in blood pressure when fed a high-salt diet or salt sensitivity. [3][4][5] High dietary salt also increases the susceptibility to kidney damage in hypertensive patients and in angiotensindependent hypertensive rats. 3,4 These parallels between patients with essential hypertension and the angiotensin infusion model make this an extremely useful model to evaluate early changes that occur in the kidney that ultimately result in ESRD.Cytochrome P450 epoxygenase metabolites are involved in the long-term regulation of blood pressure and in the response of the kidney to a high-salt diet. 6 -8 Similarly, salt-sensitive hypertension is associated with an inability of the kidney to properly increase epoxygenase levels. 8 -10 Recent studies have provided evidence that increasing epoxygenase levels have renal-and c...

Even though it has been recognized that arachidonic acid metabolites, eicosanoids, play an important role in the control of renal blood flow and glomerular filtration, several key observations have been made in the past decade. One major finding was that two distinct cyclooxygenase (COX-1 and COX-2) enzymes exist in the kidney. A renewed interest in the contribution of cyclooxygenase metabolites in tubuloglomerular feedback responses has been sparked by the observation that COX-2 is constitutively expressed in the macula densa area. Arachidonic acid metabolites of the lipoxygenase pathway appear to be significant factors in renal hemodynamic changes that occur during disease states. In particular, 12(S)- hydroxyeicosatetraenoic acid may be important for the full expression of the renal hemodynamic actions in response to angiotensin II. Cytochrome P-450 metabolites have been demonstrated to possess vasoactive properties, act as paracrine modulators, and be a critical component in renal blood flow autoregulatory responses. Last, peroxidation of arachidonic acid metabolites to isoprostanes appears to be involved in renal oxidative stress responses. The recent developments of specific enzymatic inhibitors, stable analogs, and gene-disrupted mice and in antisense technology are enabling investigators to understand the complex interplay by which eicosanoids control renal blood flow.