The SUR2B splice variant is widely expressed in the kidney, including the distal nephron where it presumably mediates, in part, potassium transport (40). However, in the proximal tubule, the combination of Kir6.1 with SUR2A and/or SUR2B forms a taurine-sensitive KATP (41). SUR2B may also couple to murine ROMK2, a Kir that resides in the cortical ascending limb and cortical collecting duct of the distal nephron (42). We hypothesized that the observed MC effects of SULF agents were mediated by specific MC KATP channels. Subsequently, using membrane preparations from rat MC, we demonstrated specific [3H]glibenclamide binding to low-affinity SUR (8). A functional Katp was subsequently demonstrated in MC. Cultured cells, following a single exposure to glibenclamide (5 ^M), initiated prolonged cycles of oscillatory cytoplasmic Ca2+ transients that were coupled to the enhancement of MC contractility (8). These observations were in alignment with results of other investigators who demonstrated similar Ca2+ oscillations in MC exposed to angiotensin II.

We subsequently cloned two SUR2 cDNAs from rat MC, a 6.7 kbp smooth muscle-type rSUR2B that had been previously described and a unique 4.8 kbp serum-regulatable MC-specific splice variant, mcSUR2B. This variant was homologous, in large part, with the larger splice variant, rSUR2B. Our findings additionally revealed expression of Kir 6.1 but not of Kir6.2 in MC (43). These studies suggest that the KATP of MC and also of isolated glomeruli are comprised of (rSUR2B/Kir6.1)4 and possibly, (mcSUR2B/Kir6.1)4 (8,43).

In this context, the marked inhibition of established high-glucose concentration-fostered ECM accumulation by glibenclamide at 10 nM is a highly relevant observation because the experimental concentrations are within the clinically relevant range for this compound (peak plasma concentration: 50-60 nM after a 5-mg dose) (44). In addition, the Kd of 6 nM for glibenclamide, as determined by complexation of SUR2B to Kir6.1 in intact cells, is consonant with this hypothesis (45). Finally, immunoreactivity for rSUR2B and mcSUR2 in primary and cloned MC (16KC2) lines as delineated by a specific antibody directed against the common C-terminal epitope of SUR2A and SUR2B further substantiates this argument (43). Thus, it is plausible that the metabolic actions of low-concentration glibenclamide on MC are mediated through KATP comprised of SUR2B/Kir6.1.


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