Angelica Fleser

Cross-Talk between the Na+-K+-ATPase and the H+-ATPase in Proximal Tubules in Suspension

The cellular energy required for the activity of the Na(+)-K(+)-ATPase and of the H(+)-ATPase was estimated in intact proximal tubules in suspension. Both the fall in oxygen consumption (directly measured) and NADH oxidation (as estimated from exogenous substrate metabolism) were measured before and following application of ouabain (1 mM) to inhibit the sodium pump, following bafilomycin (0.1 mM) to inhibit the proton pump or following a combination of these inhibitors. The data demonstrate that the sodium pump utilizes 43% and the proton pump 19% of the phosphorylating NADH turnover of canine proximal tubules studied in vitro. However, a significant and stoichiometric stimulation of one pump was observed upon inhibition of the other. The NADH turnover related to the sodium pump increased from 308 to 402 (delta = 94) mumol.g-1 wet weight.h-1 following bafilomycin application and that of the proton pump from 136 to 230 (delta = 94) following ouabain application. This stimulation was largely abolished by inhibition of the Na+/H+ exchange occurring in either direction by amiloride or methylisobutylamiloride. It is concluded that a cross-talk occurs between the basolateral sodium pumps and the proton pumps located on the brush border membrane and/or on endosomes in proximal tubules. This cross-talk appears to be mediated by Na+/H+ exchange suggesting that both the proton pump and the Na+/H+ exchanger may contribute in a cooperative fashion to the proximal secretion of protons.

Heterogeneous Metabolism and Toxicity of 4-Pentenoate along the Dog Nephron

4-Pentenoate (4P) is a short-chain fatty acid which causes a complete renal Fanconi syndrome. We have examined the mechanism of 4P toxicity along the nephron after a prolonged (30 min) exposition of isolated renal tubular segments to this agent. In proximal tubules, 4P inhibited the activity of alpha-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and beta-oxidation, but not in thick ascending limb or inner medullary collecting duct tubules in suspension. These proximal effects were accompanied by a marked oxidation of the proximal redox state, with a fall in the tissue respiration and a low content of ATP. The acetyl-CoA content of proximal tubules was simultaneously reduced. Butyrate, acetate, hexanoate or octanoate did not exert these effects. In proximal tubules the metabolism of 4P led to the tissue accumulation of 3-keto-4-pentenoyl-CoA, a known unspecific inhibitor of metabolic oxidation. This metabolite was not detectable in thick ascending limbs which metabolized 4P rapidly. No metabolism of 4P was noted in collecting ducts. We conclude that beta-oxidation probably differs in proximal and thick ascending limb tubules, allowing 4P metabolism to exert a specific toxicity in proximal tubules. A selective proximal defect in energy metabolism probably explains the Fanconi syndrome observed with exposition to 4P.

The current status of stenting pathobiology.

Stents permanently maximize the arterial lumen following percutaneous transluminal coronary angioplasty (PTCA) at the cost of a vascular injury caused by the deployment of the prosthesis. Even though clinical trials show progressive reduction of restenosis and thrombosis rates in implanted coronary stents, these two events continue to represent a potential limitation to their clinical use. This review is focused on the arterial pathobiology related to the use of permanent and temporary stents.