Apoptosis of the thick ascending limb results in acute kidney injury.

Ischemia- or toxin-induced acute kidney injury is generally thought to affect the cells of the proximal tubule, but it has been difficult to define the involvement of other tubular segments because of the widespread damage caused by ischemia/reperfusion or toxin-induced injury in experimental models. For evaluation of whether thick ascending limb (TAL)-specific epithelial injury results in acute kidney injury, a novel transgenic mouse model that expresses the herpes simplex virus 1 thymidine kinase gene under the direction of the TAL-specific Tamm-Horsfall protein promoter was generated. After administration of gancyclovir, these mice demonstrated apoptosis only in TAL cells, with little evidence of neutrophil infiltration. Compared with control mice, blood urea nitrogen and creatinine levels were at least five-fold higher in the transgenic mice, which also developed oliguria and impaired urinary concentrating ability. These findings suggest that acute injury targeted only to the TAL is sufficient to cause severe acute kidney injury in mice with features similar to those observed in humans.

A case of coexistence of three anatomical variations in the forearm: Gantzer's muscles, Martin-Gruber anastomosis, and nerve of Henle

During routine dissection of a left forearm, a simultaneous occurrence of Gantzers' muscles, Martin-Gruber anastomosis and nerve of Henle was observed in a 72 year old male. Both accessory muscle heads (Gantzers' muscles) originated from the medial epicondyle and coursed distally. The lateral accessory head crossed the ulnar artery, the Martin-Gruber anastomosis, and the branches of the median nerve to the flexors, the interosseous neurovascular bundle and the median nerve itself. The medial accessory head (Flexor Digitorum Profundus Accessorius) crossed the above structures except the last two. The Martin-Gruber anastomosis was a connection between the nerve to the Flexor Digitorum Profundus (a branch of the median nerve) and the ulnar nerve, which traversed posterior to the ulnar artery and two accessory muscle heads. The nerve of Henle originated from the ulnar nerve just proximal to joining the Martin-Gruber anastomosis, coursed distally with the ulnar artery, and supplied the skin of the distal forearm. These muscular and nervous anomalies are clinically significant since they are mutually related to one another and could compress the nerves or may be compromised during surgical procedures (AU)

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Expression of human heme oxygenase-1 in the thick ascending limb attenuates angiotensin II-mediated increase in oxidative injury.

BACKGROUND: Heme oxygenase-1 (HO-1) catalyzes the conversion of heme to bilirubin, carbon monoxide (CO), and free iron, thus controlling the level of cellular heme. The medullary thick ascending limb of the loop of Henle (TALH) is situated in a site of markedly diminished oxygen tension and, as such, is highly vulnerable to ischemic insult. We hypothesize that selective upregulation of HO-1 in TALH by gene transfer attenuates oxidative stress caused by angiotensin II (Ang II). METHODS: An adenoviral vector expressing the human HO-1 under the control of the TALH-specific promoter [Na(+)-K(+)-Cl(-) cotransporter (NKCC2 promoter)] was constructed and the cell specific expression of the recombinant adenovirus was examined using several types of cells, including endothelial, vascular smooth muscle, and TALH cells. The effects of HO-1 transduction on HO-1 expression, HO activity and the response to Ang II with respect to cyclooxygenase-2 (COX-2) up-regulation and oxidative injury [growth-stimulating hormone (GSH) levels and cell death] were determined. RESULTS: Western blot and reverse transcription-polymerase chain reaction (RT-PCR) revealed that human HO-1 was selectively expressed in primary cultured TALH cells following infection with Ad-NKCC2-HO-1. In TALH cells infected with Ad-NKCC2-HO-1, Ang II-stimulated prostaglandin E(2) (PGE(2)) levels were reduced by 40%. Ang II caused a marked decrease in GSH levels and this decrease was greatly attenuated in TALH cells transduced with Ad-NKCC2-HO-1. Moreover, Ang II-mediated DNA degradation was completely blocked by the site-specific expression of human HO-1 gene. CONCLUSION: These results indicate that TALH cell survival after exposure to oxidative stress injury may be facilitated by selective upregulation of HO-1, thusly blocking inflammation and apoptosis.

Oxygen metabolites and hypoxic renal injury: effect of mitochondrial electron transport blockade.

Isolated perfusion of the rat kidney causes hypoxic damage in the cells of the thick ascending limb of the loop of Henle. The cell damage is driven by active solute transport, which generates an imbalance of oxygen supply and demand. This injury is paradoxically prevented by adding the mitochondrial electron transport inhibitors rotenone or antimycin to the perfusion media. The present study shows that rotenone and antimycin decrease production of hydrogen peroxide in the thick ascending limb during perfusion. The findings support the hypothesis that the injury in this model is dependent on mitochondrial electron flow and suggest that mitochondrial electron flow, driven by the work of active solute transport in the presence of limited oxygen availability, may result in the generation of toxic oxygen metabolites.

Transport activity modifies thick ascending limb damage in the isolated perfused kidney.

The thick ascending limb of Henle's loop ( TAL ) develops a specific and consistent structural lesion during perfusion of the isolated rat kidney that progresses from mitochondrial swelling at 15 min to complete cellular disruption at 90 min. Because it seemed possible that damage localized to this metabolically active portion of the nephron might be correlated with cellular transport, the histology of perfused kidneys was examined when transport activity in the TAL was varied. The fraction of TAL tubules showing severe damage (44 +/- 2% in kidneys perfused with glucose) was dramatically reduced by furosemide (7 +/- 2%; P less than 0.001). The lesion was eliminated by perfusion with ouabain or by preventing glomerular filtration. On the other hand, protection of TAL cells was not obtained with the proximal diuretic acetazolamide. These results suggest that the lesion of TAL cells that develops during perfusion of the isolated kidney is influenced by the work of cellular transport.