Basolateral proteinase‐activated receptor (PAR‐2) induces chloride secretion in M‐1 mouse renal cortical collecting duct cells

Bertog, Marko; Letz, B.; Kong, Wuyi; Steinhoff, Martin; Higgins, Maria; Bielfeld-Ackermann, Andreas; Frömter, Eberhard; Bunnett, Nigel W.; Korbmacher, Christoph

doi:10.1111/j.1469-7793.1999.00003.x

Cited by 71 publications

(101 citation statements)

References 49 publications

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“…were the first to describe the presence of PAR-2 on the basolateral membrane of collecting ducts (50). The pathophysiologic role of PAR-2 activation in renal resident cells is poorly defined.…”

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-β, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-β gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-β expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN. E-mail: g.grandaliano@nephro.uniba.it

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Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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“…Currently, little is known regarding the role of PARs in the kidney, though PAR-2 is abundantly expressed in this organ (3,2). PAR-1 and PAR-2 exert apposing effects on renal blood flow and glomerular filtration rate in the isolated, perfused rat kidney (15) and thus have the capability of bidirectional control of renal hemodynamics.…”

Section: Discussionmentioning

confidence: 99%

“…Differences exhibiting P values Ͻ0.05 were considered to be statistically significant. 2 and trypsin on afferent arteriole during ANG II induced vasoconstriction. To assess the characteristics of vasorelaxation elicited by PAR-2 activation, SLIGRL-NH 2 (10 mol/l) was administered to control kidneys and to kidneys that had been pretreated with 10 mol/l ibuprofen and 100 mol/l L-NAME.…”

Section: Methodsmentioning

confidence: 99%

“…The role of PAR-2 in the kidney is largely unknown, but this area is of considerable interest as the expression levels of PAR-2 in the kidney are particularly high (3,35). PAR-2 is expressed in renal epithelia and has been shown to activate a chloride conductance in cortical collecting duct cells (2). However, PAR-2 is also highly expressed in renal vascular endothelial cells and vascular smooth muscle cells (2).…”

mentioning

confidence: 99%

“…PAR-2 is expressed in renal epithelia and has been shown to activate a chloride conductance in cortical collecting duct cells (2). However, PAR-2 is also highly expressed in renal vascular endothelial cells and vascular smooth muscle cells (2). Previous studies from our laboratory using the isolated perfused rat kidney model (15) and the in vitro perfused hydronephrotic rat kidney preparation (41) have demonstrated a potential role for PAR-2 in the regulation of renal hemodynamics, as PAR-2 activation in these preparations exerts a potent renal vasodilatory response.…”

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confidence: 99%

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Redundant signaling mechanisms contribute to the vasodilatory response of the afferent arteriole to proteinase-activated receptor-2

Wang¹,

Hollenberg²,

Loutzenhiser³

2005

American Journal of Physiology-Renal Physiology

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Renal Chloride Channels in Relation to Sodium Chloride Transport

Teulon

Planelles

Sepúlveda

et al. 2018

Comprehensive Physiology

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The many mechanisms governing NaCl absorption in the diverse parts of the renal tubule have been largely elucidated, although some of them, as neutral NaCl absorption across the cortical collecting duct or regulation through with‐no‐lysine (WNK) kinases have emerged only recently. Chloride channels, which are important players in these processes, at least in the distal nephron, are the focus of this review. Over the last 20‐year period, experimental studies using molecular, electrophysiological, and physiological/functional approaches have deepened and renewed our views on chloride channels and their role in renal function. Two chloride channels of the ClC family, named as ClC‐Ka and ClC‐Kb in humans and ClC‐K1 and ClC‐K2 in other mammals, are preponderant and play complementary roles: ClC‐K1/Ka is mainly involved in the building of the interstitial cortico‐medullary concentration gradient, while ClC‐K2/Kb participates in NaCl absorption in the thick ascending limb, distal convoluted tubule and the intercalated cells of the collecting duct. The two ClC‐Ks might also be involved indirectly in proton secretion by type A intercalated cells. Other chloride channels in the kidneys include CFTR, TMEM16A, and probably volume‐regulated LRRC8 chloride channels, whose function and molecular identity have not as yet been established. © 2019 American Physiological Society. Compr Physiol 9:301‐342, 2019.

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Basolateral proteinase‐activated receptor (PAR‐2) induces chloride secretion in M‐1 mouse renal cortical collecting duct cells

Cited by 71 publications

References 49 publications

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Redundant signaling mechanisms contribute to the vasodilatory response of the afferent arteriole to proteinase-activated receptor-2

Renal Chloride Channels in Relation to Sodium Chloride Transport

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