Protease-activated receptors in kidney disease progression

Abstract

Protease-activated receptors (PARs) are members of a well-known family of transmembrane G protein-coupled receptors (GPCRs). Four PARs have been identified to date, of which PAR1 and PAR2 are the most abundant receptors, and have been shown to be expressed in the kidney vascular and tubular cells. PAR signaling is mediated by an N-terminus tethered ligand that can be unmasked by serine protease cleavage. The receptors are activated by endogenous serine proteases, such as thrombin (acts on PARs 1, 3, and 4) and trypsin (PAR2). PARs can be involved in glomerular, microvascular, and inflammatory regulation of renal function in both normal and pathological conditions. As an example, it was shown that human glomerular epithelial and mesangial cells express PARs, and these receptors are involved in the pathogenesis of crescentic glomerulonephritis, glomerular fibrin deposition, and macrophage infiltration. Activation of these receptors in the kidney also modulates renal hemodynamics and glomerular filtration rate. Clinical studies further demonstrated that the concentration of urinary thrombin is associated with glomerulonephritis and type 2 diabetic nephropathy; thus, molecular and functional mechanisms of PARs activation can be directly involved in renal disease progression. We briefly discuss here the recent literature related to activation of PAR signaling in glomeruli and the kidney in general and provide some examples of PAR1 signaling in glomeruli podocytes.

Keywords: calcium transient; chronic kidney disease; perivascular cells; serine proteases.

Fig. 1.

A: immunohistochemical staining for protease-activated receptor 1 (PAR1) and PAR2 expression in the Dahl salt-sensitive rat kidney cortex. Experiments were performed as previously published (26). Antibodies were obtained from Abbiotec (Ab #251324 and Ab #251547 for PAR1 and PAR2 correspondingly). Scale bar = 50 μm. Animal protocols were approved by Medical College of Wisconsin Institutional Animal Care and Use Committee. B: stimulation of PARs by short peptide fragments specific to PAR1 evokes calcium transients in freshly isolated rat glomerular podocytes. Calcium transients obtained by ratiometric confocal imaging (excitation 488 nm and emission filters 525/25 and 650/25 nm for Fluo-4 and Fura Red, respectively) in response to a bath application of a selective PAR1 agonist TFLLR-NH2 (50 μM) followed by an application of ATP (2.5 μM; positive control). Assessment of calcium transients was performed as previously published (25).