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...

. Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol 295: F556 -F567, 2008. First published May 14, 2008 doi:10.1152/ajprenal.00340.2007.-We investigated which of the NaCl transporters are involved in the maintenance of salt-sensitive hypertension. Milan hypertensive (MHS) rats were studied 3 mo after birth. In MHS, compared with normotensive strain (MNS), mRNA abundance, quantified by competitive PCR on isolated tubules, was unchanged, both for Na ϩ /H ϩ isoform 3 (NHE3) and Na. These results were confirmed by Western blots, which revealed: 1) unchanged NHE3 in the cortex and NKCC2 in the outer medulla; 2) a significant increase (52%, n ϭ 6, P Ͻ 0.001) of NCC in the cortex; 3) ␣-and ␤-sodium channels [epithelial Na ϩ channel (ENaC)] unaffected in renal cortex and slightly reduced in the outer medulla, while ␥-ENaC remained unchanged. Pendrin protein expression was unaffected. The role of NCC was reinforced by immunocytochemical studies showing increased NCC on the apical membrane of DCT cells of MHS animals, and by clearance experiments demonstrating a larger sensitivity (P Ͻ 0.001) to bendroflumethiazide in MHS rats. Kidneyspecific chloride channels (ClC-K) were studied by Western blot experiments on renal cortex and by patch-clamp studies on primary culture of DCT dissected from MNS and MHS animals. Electrophysiological characteristics of ClC-K channels were unchanged in MHS rats, but the number of active channels in a patch was 0.60 Ϯ 0.21 (n ϭ 35) in MNS rats and 2.17 Ϯ 0.59 (n ϭ 23) in MHS rats (P Ͻ 0.05). The data indicate that, in salt-sensitive hypertension, there is a strong upregulation, both of NCC and ClC-K along the DCT, which explains the persistence of hypertension. type 3 sodium/hydrogen exchanger; sodium-potassium 2 chloride cotransporter; sodium-chloride cotransporter; epithelial sodium channel; kidney-specific chloride channel; pendrin; aldosterone HYPERTENSION IS THE MOST IMPORTANT risk factor for diseases of several organs, including heart, brain, and kidney. Despite the impressive number of studies, the etiology of hypertension is still incompletely understood. However,

The reported data indicate that effective DOPET protection from CsA-induced oxidative stress is associated with a mild effect on histological damages and does not affect the altered glomerular function and the hypertension, thus indicating that kidney injury by CsA is only in part dependent on oxidative stress.

Ochratoxin A (OTA) is a powerful mycotoxin found in various foods and feedstuff, responsible for subchronic and chronic toxicity, such as nephrotoxicity, hepatotoxicity, teratogenicity, and immunotoxicity to both humans and several animal species. The severity of the liver damage caused depends on both dose and duration of exposure. Several studies have suggested that oxidative stress might contribute to increasing the hepatotoxicity of OTA, and several antioxidants, including curcumin (CURC), have been tested to counteract the toxic hepatic action of OTA in various classes of animals. Therefore, the present study was designed to evaluate the protective effect of CURC, a bioactive compound with different therapeutic properties on hepatic injuries caused by OTA in rat animal models. CURC effects were examined in Sprague Dawley rats treated with CURC (100 mg/kg), alone or in combination with OTA (0.5 mg/kg), by gavage daily for 14 days. At the end of the experiment, rats treated with OTA showed alterations in biochemical parameters and oxidative stress in the liver. CURC dosing significantly attenuated oxidative stress and lipid peroxidation versus the OTA group. Furthermore, liver histological tests showed that CURC reduced the multifocal lymphoplasmacellular hepatitis, the periportal fibrosis, and the necrosis observed in the OTA group. This study provides evidence that CURC can preserve OTA-induced oxidative damage in the liver of rats.

The proximal tubule uses a complex process of apical acid secretion and basolateral bicarbonate absorption to regulate both luminal acidification and fluid absorption. One of the primary regulators of apical acid secretion is the luminal sodium-hydrogen exchanger expressed along the apical membrane of the proximal tubule. Similarly, the calcium-sensing receptor (CaSR) is also located along the luminal membrane of the proximal tubule. Here we investigated the role of CaSR in proton secretion and fluid reabsorption in proximal tubules by modulating luminal calcium concentration, using both in vivo micropuncture in rats and in vitro perfused mouse proximal tubules. Using CaSR knockout mice and a calcimimetic agent, we found that increased proton secretion and fluid reabsorption were CaSR dependent. Activating CaSR by either raising the luminal calcium ion concentration or by the calcimimetic caused a concomitant increase in sodium-dependent proton extrusion and fluid reabsorption, whereas in proximal tubules isolated from CaSR knockout mice varying calcium ion concentration had no effect. Application of a calcimimetic in lower concentrations of calcium ion stimulated these processes in vitro and in vivo. Thus, in both rats and mice, increased luminal calcium concentration leads to enhanced fluid reabsorption in the proximal tubule, a process related to activation of CaSR.

Administration of rMnSOD prevents CsA-mediated impairment of the GFR along with morphological alteration. This effect could be related to the inhibition of ROS.

In this work, we investigated the effects of red orange and lemon extract (RLE) on ochratoxin A (OTA)‐induced nephrotoxicity. In particular, we analyzed the change in renal function and oxidative stress in Sprague–Dawley rats treated with OTA (0.5 mg/kg body weight, b.w.) and with RLE (90 mg/kg b.w.) by oral administration. After OTA treatment, we found alterations of biochemical and oxidative stress parameters in the kidney, related to a severe decrease of glomerular filtration rate. The RLE treatment normalized the activity of antioxidant enzymes and prevented the glomerular hyperfiltration. Histopathological examinations revealed glomerular damages and kidney cortex fibrosis in OTA‐rats, while we observed less severe fibrosis in OTA plus RLE group. Then, we demonstrated that oxidative stress could be the cause of OTA renal injury and that RLE reduces this effect.

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