Selectively reduced expression of thick ascending limb Tamm-Horsfall protein in hypothyroid kidneys

Hypothyroidism causes major changes in the kidney by affecting its growth, structure, function, and biosynthesis of its specific gene products. As a consequence, the nephron shows a selective hypotrophy in the medullary portion of the thick ascending limb (TAL). Contrastingly, we have shown earlier that the abundance of the major ion transporter of the TAL, the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) was increased when related to kidney function in the hypothyroid organism. Synthesis of Tamm-Horsfall protein (THP), the most abundant urinary protein produced in the TAL, has been suggested to interfere with TAL function. We therefore studied the localization and synthesis rate of THP in the hypothyroid kidney. We used rats chronically treated with methimazole. Kidneys were processed for western blotting and histochemical evaluation. Morphologically the hypothyroid TAL displayed a selectively reduced epithelial cell height of its medullary portion. This was paralleled by decreased THP immunostaining and mRNA abundance. Western blotting indicated a 40% reduction in renal THP content (P<0.005), and daily urinary THP excretion was 68% lower than in controls (P<0.05). T3 substitution restored these parameters. To further confirm that changes were specific for THP and not merely the consequence of reduced kidney growth, the abundance of barttin, another distal tubular protein related to chloride transport, was tested as well. Barttin was increased by 43% in the hypothyroid rats. Together with our previous results showing increased NKCC2 expression in hypothyroidism, these results demonstrate a selective decrease in medullary THP synthesis. We suggest a potential involvement of THP in the renal functional changes associated with hypothyroidism.