Increased intrarenal expression of sodium-dicarboxylate cotransporter-1 in nephrolithiasis patients with acidic urine pH

Background: Low urinary excretion of citrate is a major risk in Thai kidney stone patients. Reabsorption of citrate at renal proximal tubules requires sodium-dicarboxylate cotransporter-1 (NaDC-1).

Objectives: We investigated the expression of NaDC-1 in stone-containing kidneys and evaluated the association of NaDC-1 expression with urine pH. Expression of NaDC-1 protein in acid-treated human proximal renal cells (HK-2 cells) was also studied.

Methods: Twenty-four patients with nephrolithiasis aged 50.61 ± 13.30 years (9 males, 15 females) were recruited. Twenty-four hours urine samples were collected from all patients. Expression of NaDC-1 in renal tissues and HK-2 cells was determined by immunohistochemistry and Western blotting, respectively.

Results: NaDC-1 was expressed mainly in proximal renal tubular cells. Tubular cells in the medullary region were weakly positive for NaDC-1. The intensity of NaDC-1 expression varied among nephrolithic renal tissues and was categorized into weak (6/24, 25%), intermediate (10/24, 42%), and high (8/24, 33%) expression. A trend of decreased urine pH in patients with increased NaDC-1 expression was observed. When the expression of NaDC-1 was recategorized into low (16/24) and high (8/24) expression, patients with high NaDC-1 expression had significantly lower urine pH than those with low NaDC-1 expression. Acid-treated HK-2 cells (pH 6.8) showed significantly higher expression of NaDC-1 compared with the control nontreated cells (pH 7.4). Significant association between urinary citrate and urine pH was not found. Also, significant association between urinary citrate and intrarenal NaDC-1 expression was not revealed.

Conclusion: NaDC-1 was principally expressed in proximal renal tubules of stone-bearing kidneys. High expression of NaDC-1 was associated with low urine pH. To our knowledge, this is the first report of NaDC-1 expression in the kidneys of nephrolithiasis patients. We experimentally confirmed that acid conditions upregulated the expression of NaDC-1 in the human proximal tubular cells.