Adenosine is a determinant of metabolic control of organ function increasing oxygen supply through the A2 class of adenosine receptors and reducing oxygen demand through A1 adenosine receptors (A1AR). In the kidney, activation of A1AR in afferent glomerular arterioles has been suggested to contribute to tubuloglomerular feedback (TGF), the vasoconstriction elicited by elevations in [NaCl] in the macula densa region of the nephron. To further elucidate the role of A1AR in TGF, we have generated mice in which the entire A1AR coding sequence was deleted by homologous recombination. Homozygous A1AR mutants that do not express A1AR mRNA transcripts and do not respond to A1AR agonists are viable and without gross anatomical abnormalities. Plasma and urinary electrolytes were not different between genotypes. Likewise, arterial blood pressure, heart rates, and glomerular filtration rates were indistinguishable between A1AR ؉/؉ , A1AR

The present studies were undertaken to determine the effect of dietary salt intake on the renal expression of cyclooxygenase-1 (COX-1) and -2 (COX-2). Protein levels were assessed by Western blotting, and mRNA expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR) on cDNA prepared from kidney regions, dissected nephron segments, and cultured renal cells. Both isoforms were expressed at high levels in inner medulla (IM), with low levels detected in outer medulla and cortex. COX-1 mRNA was present in the glomerulus and all along the collecting duct, whereas COX-2 mRNA was restricted to the macula densa-containing segment (MD), cortical thick ascending limb (CTAL), and, at significantly lower levels, in the inner medullary collecting duct. Both isoforms were highly expressed at high levels in cultured medullary interstitial cells and at lower levels in primary mesangial cells and collecting duct cell lines. Maintaining rats on a low- or high-NaCl diet for 1 wk did not affect expression of COX-1. In IM of rats treated with a high-salt diet, COX-2 mRNA increased 4.5-fold, and protein levels increased 9.5-fold. In contrast, cortical COX-2 mRNA levels decreased 2.9-fold in rats on a high-salt diet and increased 3.3-fold in rats on a low-salt diet. A low-salt diet increased COX-2 mRNA 7.7-fold in MD and 3.3-fold in CTAL. Divergent regulation of COX-2 in cortex and medulla by dietary salt suggests that prostaglandins in different kidney regions serve different functions, with medullary production playing a role in promoting the excretion of salt and water in volume overload, whereas cortical prostaglandins may protect glomerular circulation in volume depletion.

The peroxisome proliferator-activated receptor subtype ␥ (PPAR␥) ligands, namely the synthetic insulin-sensitizing thiazolidinedione (TZD) compounds, have demonstrated great potential in the treatment of type II diabetes. However, their clinical applicability is limited by a common and serious side effect of edema. To address the mechanism of TZD-induced edema, we generated mice with collecting duct (CD)-specific disruption of the PPAR␥ gene. We found that mice with CD knockout of this receptor were resistant to the rosiglitazone-(RGZ) induced increases in body weight and plasma volume expansion found in control mice expressing PPAR␥ in the CD. RGZ reduced urinary sodium excretion in control and not in conditional knockout mice. Furthermore, RGZ stimulated sodium transport in primary cultures of CD cells expressing PPAR␥ and not in cells lacking this receptor. These findings demonstrate a PPAR␥-dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention.roziglitazone ͉ Cre recombinase ͉ Evans blue technique T hiazolidinediones (TZDs), synthetic insulin-sensitizing drugs that include troglitazone, pioglitazone, and rosiglitazone (RGZ), are highly effective in the treatment of type II diabetes. TZDs are believed to mediate their antidiabetic effect via activation of peroxisome proliferator-activated receptor ␥ (PPAR␥) (1). In addition to lowering blood glucose, these drugs also benefit cardiovascular parameters, such as blood pressure and endothelial function (2, 3). However, fluid retention, presented as rapid weight gain, and peripheral and pulmonary edema have emerged as the most common and serious side effects of TZDs (4-6). Global awareness of this side effect has increased as a result of the growing number of reported cases. In a recent issue of Circulation (7), the American Heart Association and American Diabetes Association jointly issued a Consensus Statement commenting on the safety of TZD as related to edema. The mechanisms of fluid retention in patients treated with TZDs are poorly understood and may involve a number of factors, including reduction of urinary sodium excretion (8), alteration of endothelial permeability (9), increased sympathetic nervous system activity (10), or altered interstitial ion transport (11). To evaluate the relative contributions of these individual mechanisms, tissue-or cell-type-specific approaches are needed in carefully designed studies.PPARs are a group of zinc finger-containing transcription factors, representing a family of the nuclear hormone receptor gene superfamily. To date, three subtypes of PPARs encoded by different genes have been described from several species: PPAR␣, -␤͞␦, and -␥ (12, 13). They share a high degree of similarity in their overall amino acid sequences, particularly in the DNA-binding domain (14). The three isoforms of the PPARs heterodimerize with retinoid X receptor, bind to the same peroxisome proliferatorresponsive element in the promoter regions of their target genes, and modulate gene transcripti...