Effects of parathyroid hormone on renal tubular proteinases

Parathyroid hormone (PTH) has been implicated to exert detrimental effects on remnant nephrons in chronic renal failure. The present investigation addressed the influence of PTH on the proteolytic capacity of isolated proximal tubules both from normal (SHAM) and partially nephrectomized rats (5/6-NX). Proteolytic activities were measured either against azocasein (pH 5.4) or with specific fluorogenic peptidyl substrates for individual cysteine proteinases. Azocaseinolytic activity was enhanced 6 weeks after 5/6-NX in tubules (SHAM 19.0 +/- 1.0 vs. 5/6-NX 24.4 +/- 1.5 U/mg protein), while thereafter activities declined progressively with time (5/6-NX 16 weeks: 12.9 +/- 1.2 U/mg protein). This loss in proteolytic activity could almost completely be prevented by parathyroidectomy (PTX) (5/6-NX + PTX 16 weeks: 18.6 +/- 1.1 U/mg protein). By contrast, severe hyperparathyroidism (induced by a low calcium/high phosphorus diet fed for 6 weeks) in 5/6-NX animals resulted in a significant decline in proteolytic activities in remnant tubules (5/6-NX 24.4 +/- 1.5 vs. 5/6-NX+diet 16.4 +/- 1.9 U/mg protein). When specific activities of tubular cathepsins were measured in healthy rats who had received exogenous PTH, each individual cysteine proteinase (cathepsin L: -42%; cathepsin B: -27%; cathepsin H: -51%) was suppressed. This effect of PTH could readily be abolished by the simultaneous administration of verapamil. These results suggest that chronic PTH excess exerts a suppressive effect on tubular proteinase activities both in normal and partially nephrectomized rats. This PTH effect seems to be mediated by an increase of cytosolic calcium.