Abstract-Proximal tubule reabsorption is regulated by systemic and intrinsic mechanisms, including locally produced autocoids. Superoxide, produced by NADPH oxidase enhances NaCl transport in the loop of Henle and the collecting duct, but its role in the proximal tubule is unclear. We measured proximal tubule fluid reabsorption (Jv) in WKY rats and compared that with Jv in the spontaneously hypertensive rat (SHR), a model of enhanced renal superoxide generation. Rats were treated with the NADPH oxidase inhibitor apocynin (Apo) or with small interfering RNA for p22 phox , which is the critical subunit of NADPH oxidase. Jv was lower in SHR compared with Wistar-Kyoto rats (WKY; WKY: 2.3Ϯ0.3 vs SHR: 1.1Ϯ0.2 nL/min per millimeter; nϭ9 to 11; PϽ0.001). Apo and small interfering RNA to p22 phox normalized Jv in SHRs but had no effect in WKY rats. Jv was reduced in proximal tubules perfused with S-1611, a highly selective inhibitor of the Na ϩ /H ϩ exchanger 3, the major Na ϩ uptake pathway in the proximal tubule, in WKY rats but not in SHRs. Pretreatment with Apo restored an effect of S-1611 to reduce Jv in the SHRs (SHRϩApo: 2.9Ϯ0.4 vs SHRϩApoϩS-1611: 1.0Ϯ0.3 nL/min per millimeter; PϽ0.001). However, because expression of the Na ϩ /H ϩ exchanger 3 was similar between SHR and WKY rats, this suggests that superoxide affects Na ϩ /H ϩ exchanger 3 activity. Direct microperfusion of Tempol or Apo into the proximal tubule also restored Jv in SHRs. In conclusion, superoxide generated by NADPH oxidase inhibits proximal tubule fluid reabsorption in SHRs. This finding implies that proximal tubule fluid reabsorption is regulated by redox balance, which may have profound effects on ion and fluid homeostasis in the hypertensive kidney. Key Words: proximal reabsorption Ⅲ superoxide Ⅲ Tempol Ⅲ apocynin Ⅲ hypertension I n the kidney, the proximal tubule (PT) reabsorbs 60% to 70% of filtered NaCl and fluid. Therefore, changes in PT reabsorption can have profound effects on renal and body fluid balance and may contribute to the development of hypertension. The normal kidney protects against acute increases in blood pressure by excreting NaCl rapidly. The PT is thought to mediate much of this pressure-natriuresis response. In young spontaneously hypertensive rats (SHRs), before the onset of hypertension, expression of the major Na ϩ transport systems in the PTs was higher 1 and Na ϩ excretion was lower compared with normotensive rats (Wistar-Kyoto [WKY]). 2 This was accompanied by an increase in fluid reabsorption in the PT in young (5-week-old) prehypertensive SHRs compared with WKY. These observations suggest that an exaggerated NaCl and fluid reabsorption in the PT may contribute to the development of hypertension in young SHRs, which persists in the adult animal. However, the increased reabsorption seen in young animals is not consistently observed in adult SHRs. For example, in 7-and 12-week-old SHRs, at a time when hypertension was established, baseline proximal tubule fluid reabsorption (Jv) in the PT was lower compared with that...

Adenosine mediates Na+ reabsorption in the proximal tubule (PT) and other segments by activating adenosine type 1 receptors (A1-AR). We tested the hypothesis that A1-AR in the PT is regulated by salt intake and participates in the kidney adaptation to changes in salt intake. Absolute fluid reabsorption (Jv) was measured by direct in vivo microperfusion and recollection in rats maintained on low (LS; 0.03% Na, wt/wt)-, normal (NS; 0.3% Na)-, and high-salt (HS; 3.0% Na) diets for 1 wk. The effect of microperfusion of BG9719 a highly selective inhibitor of A1-ARs or adenosine deaminase (AD), which metabolizes adenosine, was measured in each group. Jv was higher in PT from LS rats (LA: 2.8 +/- 0.2 vs. NS: 2.1 +/- 0.2 nl.min(-1).mm(-1), P < 0.001). Jv in HS rats was not different from NS. BG9719 reduced Jv in LS rats by 66 +/- 6% (LS: 2.8 +/- 0.2 vs LS+CVT: 1.3 +/- 0.3 nl.min(-1).mm(-1), P < 0.001), which was greater than its effect in NS (45 +/- 4%) or HS (41 +/- 4%) rats. AD reduced Jv similarly, suggesting that A1-ARs are activated by local production of adenosine. Expression of A1-AR mRNA and protein was higher (P < 0.01) in microdissected PTs in LS rats compared with NS and HS. We conclude that A1-ARs in the PT are increased by low salt intake and that A1-AR participates in the increased PT reabsorption of solute and fluid in response to low salt intake.

Since inflammation has been linked to carcinogenic events, discovery of relevant biomarkers may have important preventative implications. Procalcitonin (ProCT) has been shown to be an important prognostic biomarker in severe inflammatory conditions, but there is no data regarding its biomarker role, if any, beyond the acute phase. In a recent study published in BMC Medicine, Cotoi et al. analyzed whether serum ProCT levels in healthy individuals are associated with mortality outcomes. The results are affirmative in that baseline ProCT was shown to be strongly and independently associated with all-cause and cancer mortality and with the incidence of colon cancer in men. By contrast, the study indicated that high sensitivity C-reactive protein was independently associated with cardiovascular mortality but not with cancer mortality in men. Thus, baseline levels of ProCT appear to have prognostic biomarker implications potentially related to its emerging biomediator action(s).

An elevation in angiotensin II (Ang II) levels is a common occurrence in spontaneously hypertensive rats (SHRs). Infusions of Ang II and a high salt diet increase the activity of NADPH oxidase that stimulates superoxide anion (O −2 ) generation and increases the expression of certain subunits of NADPH oxidase. Apocynin, an NADPH oxidase inhibitor with antihypertensive effects, is able to inhibit the release of superoxide anion by inhibiting NADPH oxidase activity and blocking the migration of p47 phox to the mitochondrial membrane. The aim of our study was to evaluate the antihypertensive effects of apocynin in SHRs and Wistar rats (WKYs) using a micropuncture technique. After microperfusion of both the proximal and distal tubules, we found that SHRs treated with apocynin showed a decrease in the free-flow collection of the proximal tubule (PT), which was not affected in WKYs. Moreover, significant differences were not demonstrated in the distal tubule (DT), probably due a mechanism of compensation that occurs in the loop of Henle. In conclusion, it is possible that the mechanisms of reabsorption in the PT are controlled by the interactions of O −2 and nitric oxide (NO). These data could suggest a higher activity of NADPH oxidase and increase in reactive oxygen species (ROS) production in the PT during hypertension.

Given the burden of kidney disease in African Americans, the discovery of safe and effective medical products to slow the progression of kidney disease and reduce the risk for kidney failure would have a tremendous impact on this population. Differences in response to treatment have been observed in African Americans, highlighting the importance of studying medical products in African Americans. Although historically the African American community has not been well represented in clinical trials, efforts are underway to address this issue. Recent advances in understanding the genetic contributions to disease progression in African Americans, including the discovery of risk variants in the apolipoprotein L1 gene (APOL1), raise the possibility of using genetic information to better tailor treatments for African Americans. One could envision developing therapies that target these variants or possibly using them to help enrich trial populations with patients more likely to experience disease progression.