A multidomain, multifunctional 230-kDa extracellular matrix (ECM)
protein, hensin, regulates the adaptation of rabbit kidney to
metabolic acidosis by remodeling collecting duct intercalated cells. Conditional deletion of hensin in intercalated cells of the mouse kidney leads to
distal renal tubular acidosis and to a significant reduction in the number of cells expressing the basolateral
chloride-bicarbonate exchanger kAE1, a characteristic marker of α-intercalated cells. Although hensin is secreted as a monomer, its polymerization and ECM assembly are essential for its role in the adaptation of the kidney to
metabolic acidosis.
Galectin-3, a unique
lectin with specific affinity for β-galactoside
glycoconjugates, directly interacts with hensin. Acidotic rabbits had a significant increase in the number of cells expressing
galectin-3 in the collecting duct and exhibited colocalization of
galectin-3 with hensin in the ECM of microdissected tubules. In this study, we confirmed the increased expression of
galectin-3 in acidotic rabbit kidneys by real-time RT-PCR.
Galectin-3 interacted with hensin in vitro via its
carbohydrate-binding COOH-terminal domain, and the interaction was competitively inhibited by
lactose, removal of the COOH-terminal domain of
galectin-3, and deglycosylation of hensin. Galectin-9, a
lectin with two
carbohydrate-recognition domains, is also present in the rabbit kidney; galectin-9 partially oligomerized hensin in vitro. Our results demonstrate that
galectin-3 plays a critical role in hensin ECM assembly by oligomerizing secreted monomeric hensin. Both the NH₂-terminal and COOH-terminal domains are required for this function. We suggest that in the case of galectin-3-null mice galectin-9 may partially substitute for the function of
galectin-3.