Tamm-Horsfall protein protects urothelial permeability barrier

Abstract

Objectives To test whether the presence of Tamm-Horsfall protein (THP) can limit the injury caused by low-molecular-weight (LMW) urinary cations using an in vivo rat bladder injury model. Previous studies have shown that normal urine contains LMW cations toxic to cultured bladder cells and that THP, a ubiquitous urinary glycoprotein, protects against this cytotoxic effect. THP may sequester and subsequently neutralize these toxic urinary cations. Methods A dialysis product of LMW (greater than 100 but less than 3500) was prepared from pooled 24-hour urine samples from healthy volunteers and evaluated for urothelial cell cytotoxicity. The LMW toxic factor (TF) was instilled into the bladders of Sprague-Dawley rats (n = 9) after recording the baseline urodynamic parameters, primarily nonvoiding contractions (NVCs). We also evaluated the ability of THP to block abnormal physiologic activity indicative of bladder injury caused by exposure to the TF (greater than 100 but less than 3500 molecular weight) by co-instillation of the TF with THP. Results The TF had a significant cytotoxic effect in cultured rat ( P <0.01) and human ( P <0.01) bladder epithelial cells. Rat bladder NVCs increased significantly over baseline contractility when potassium chloride was infused after TF (1.68 ± 0.11 NVC/min; P <0.0001) but not after infusion of THP plus TF (0.28 ± 0.085 NVC/min). Conclusions Normal urine contains a cationic factor that appears to increase urothelial permeability by injuring the mucosa, allowing potassium ions to penetrate the urothelium and depolarize underlying nerves and muscle. THP appears to neutralize the LMW fraction electrostatically and attenuate urothelial damage, resulting in suppression of potassium chloride-mediated bladder hyperactivity.