5). Incubation with a suprapharmacological dose of the drug (100 ��M), two orders of magnitude higher than the maximum concentration of total selleck catalog rosiglitazone reached in human plasma after an 8-mg oral dose (14), led to a significant increase in apical Na+/H+ activity, but this increase was not different in control and lipid-loaded cells (Fig. 5). DISCUSSION One renal manifestation of the metabolic syndrome in both humans and ZDF rats is an excessively acidic urine, attributed in part to impaired urinary NH4+ excretion (6, 9, 16, 27, 28). Decreased NHE3 expression and activity in the proximal tubule brush border contribute to this defect in ZDF rats, although other factors such as decreased glutamine metabolism due to mitochondrial substrate competition by excess intracellular FFA could also play a role (6).

Impaired luminal acid extrusion via NHE3 could also explain the reduced excretion of urinary citrate in ZDF rats, since intracellular acidification in the proximal tubule upregulates both citrate reabsorption and citrate metabolism (1, 29). Hypocitraturia in these animals cannot be attributed to differences in acid or alkali intestinal absorption, given that urinary sulfate and potassium were not different in ZDF and lean rats. These functional abnormalities are accompanied by renal steatosis with predominant tubular localization in ZDF rats and can be reproduced in part in a cell culture model of proximal tubule lipotoxicity, OKP cells incubated with FFA (6). Renal steatosis and lipotoxicity may thus be an important factor in the pathophysiology of renal acidification defects associated with the metabolic syndrome.

We have shown that TZD treatment in ZDF rats reduces renal steatosis. The antisteatotic action of TZD has been described in humans and animal models of the metabolic syndrome in the liver, heart, and skeletal muscle (4, 22, 38, 47, 52, 57), but to our knowledge the effect of TZD on renal triglyceride content has not been previously examined. Reduction of renal fat with TZD in ZDF rats was accompanied by a shift in urinary NH4+, pH, TA, and citrate to levels comparable to their lean littermates and led to a commensurate increase in brush-border NHE3 protein and activity. No effect of TZD on urinary acidification parameters was noted in lean control rats, in the absence of renal steatosis.

The concurrent reduction in renal triglycerides and normalization of NHE3 and urinary parameters strongly suggest correction of functional abnormalities with renal lipid mobilization, and thus support the causal relationship between renal steatosis and urinary acidification defects in vivo. The effect of TZD on renal steatosis and GSK-3 functional abnormalities is likely attributable to PPAR�� activation in the adipose tissue, which in turn decreases nonadipose tissue lipotoxicity by redistributing lipids to adipocytes (44, 55).