High mobility group box 1 inhibits HCO3- absorption in medullary thick ascending limb through RAGE-Rho-ROCK-mediated inhibition of basolateral Na+/H+ exchange.

High mobility group box 1 inhibits HCO3- absorption in medullary thick ascending limb through RAGE-Rho-ROCK-mediated inhibition of basolateral Na+/H+ exchange. Am J Physiol Renal Physiol. 2016 Jun 29;:ajprenal.00185.2016 Authors: Watts BA, George T, Badalamenti A, Good DW Abstract High mobility group box 1 (HMGB1) is a nuclear protein released extracellularly in response to infection or injury, where it activates immune responses and contributes to the pathogenesis of kidney dysfunction in sepsis and sterile inflammatory disorders. Recently we demonstrated that HMGB1 inhibits HCO3 (-) absorption in perfused rat medullary thick ascending limbs (MTAL) through a basolateral RAGE-dependent pathway that is additive to TLR4-ERK-mediated inhibition by LPS. Here, we examined signaling and transport mechanisms that mediate inhibition by HMGB1. Inhibition of HCO3 (-) absorption by HMGB1 was eliminated by the Rho-associated kinase (ROCK) inhibitor Y27632 and by a specific inhibitor of Rho, the major upstream activator of ROCK. HMGB1 increased RhoA and ROCK1 activity. HMGB1-induced ROCK1 activation was eliminated by the RAGE antagonist FPS-ZM1 and by inhibition of Rho. The Rho and ROCK inhibitors had no effect on inhibition of HCO3 (-) absorption by bath LPS. Inhibition of HCO3 (-) absorption by HMGB1 was eliminated by bath amiloride, 0 Na(+) bath, and the F-actin stabilizer jasplakinolide, three conditions that selectively prevent inhibition of...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research