Calcium-mediated proximal tubular injury—what is the role of cysteine proteases?

Numerous studies over the past 15 years in different injury models and cell types have demonstrated an increase in cytosolic calcium in renal epithelial cell injury. Some of these studies are summarized in Table 1. However, despite these studies, crucial questions to implicate calcium as the primary factor in cell injury have remained. Does the increase in calcium precede the injury? Does preventing the rise in cytosolic calcium attenuate the injury? Recent studies have provided insight into these questions. Both Weinberg et al. [1] and Kribben et al. [2] conclusively demonstrated in proximal tubules that hypoxia is associated with a rise in cytosolic calcium which precedes any evidence of membrane damage. To further support a pathogenetic role of intracellular calcium, calcium-mediated injury is also reversible with reoxygenation [2], a calcium chelator to lower intracellular calcium [2] and by lowering the extracellular calcium concentration [3]. ... There is also compelling evidence for the role of cellular calcium in the pathophysiology of ischaemic acute renal failure (ARF) in vivo. Chemically dissimilar calcium channel blockers (CCB) are effective in preventing or attenuating the course of experimental ischaemic ARF [4]. Vascular perturbations in experimental ischaemic ARF were found to be associated with an increase in calcium in afferent arterioles from ischaemic as compared to control kidneys [5]. On the background of these experimental results, the efficacy of CCB has been shown in preventing ARF associated with cadaveric transplantation and radiocontrast media [6].