Huamin Wang, Hubert Zajicek, Vijay Kumar, Paul Wilson, and Moshe Levi

Department of Medicine, The University of Texas Southwestern Medical Center at Dallas and Department of Veterans Affairs Medical Center, Dallas, Texas 75216, USA

Received 1/13/97; Accepted 1/13/97; On-line 02/01/96

3. Role of Cholesterol in the Regulation of Renal Phosphate Transport

The first evidence that alterations in BBM cholesterol content may modulate Na/Pi cotransport activity was provided by Molitoris et al. (9) who showed that in rats chronically fed a low Pi diet the adaptive increase in the renal tubular reabsorption of phosphate was associated with a decrease in BBM cholesterol content. In fact, the authors demonstrated an inverse linear relationship between the tubular reabsorption of Pi and BBM cholesterol content. Since a decrease in BBM cholesterol also resulted in an increase in BBM fluidity, this study suggested that either a decrease in BBM cholesterol content or an increase in BBM fluidity could play a role in the regulation of Na/Pi transport. Subsequent studies with isolated BBM and/or renal tubular cells grown in culture demonstrated that a direct increase in membrane fluidity indeed results in an increase in Na/Pi cotransport activity (10-12). Further studies in our laboratory confirmed the findings of Molitoris et al., and also showed that in aged rats the decrease in the renal tubular reabsorption of Pi was associated with an increase in BBM cholesterol content (Figure 1) and a decrease in BBM fluidity (13).

Figure 1: There is an inverse relationship between BBM Cholesterol content and BBM Na/Pi cotransport activity in young versus aged rats and in rats fed a low Pi versus a high Pi diet. Data adapted from References 13 and 14.

In studies designed to determine if changes in BBM cholesterol content per se do play a role in the modulation of BBM Na/Pi cotransport (14), we first showed that in BBM isolated from young rats chronically fed a low Pi diet in vitro enrichment with cholesterol, to levels present in young rats chronically fed a high Pi diet, completely reversed the adaptive increase in Na/Pi cotransport activity (Figure 2).

Figure 2: In rats which have been fed a low Pi diet, in vitro enrichment of the isolated BBM with cholesterol, to levels found in rats fed a normal Pi diet, reverses the adaptive increases in BBM Na/Pi cotranport activity (right panel) and BBM fluidity (inversely related to the fluorescence polarization of diphenylhexatriene, r_DPH, left panel). Adapted from Reference 14.

In subsequent studies, we showed that in BBM isolated from young rats in vitro enrichment with cholesterol, to levels present in aged rats, reproduced the age-related decrease in Na/Pi cotransport activity (Figure 3). Of interest, this effect of cholesterol was specific and selective for Na/Pi cotransport, as cholesterol enrichment had no effect on BBM Na/glucose, Na/proline, and Na/sulfate cotransport, or Na/H exchange activities (14).