Role of chymase in diabetic nephropathy

Abstract

Chymase is an alternative pathway for angiotensin-converting enzyme in angiotensin II (Ang II) formation, and its expression is increased in human diabetic kidneys and in human mesangial cells (MCs) stimulated with high glucose. In addition, chymase activates transforming growth factor (TGF-β1) via an Ang II-independent pathway. The aim of this study was to evaluate the role of chymase on TGF-β1 activation in diabetic rats and in rat MCs (RMCs) stimulated with high glucose (HG). Diabetes was induced in male Wistar rats by streptozotocin (60 mg/kg, intravenous). After 30 (D30) or 60 (D60) days, chymase activity and the expression of profibrotic markers were evaluated. RMCs were stimulated with HG in the presence or absence of 50 μmol/L chymostatin, a chymase inhibitor, or 100 nmol/L of losartan, an Ang II antagonist. Chymase activity and expression increased in D60 kidneys, with increased expression of fibronectin, type I and III collagen, TGF-β1 and Smad 3 and with no change in Smad 7 expression. RMCs exposed to HG presented increases in chymase activity and expression, together with upregulation in fibrosis markers and in the TGF-β1 signaling pathway. All these effects were reversed by chymostatin and by losartan, but type 1 angiotensin II receptor blockade did not interfere with the Smad 3 and 7 pathway. Similar to HG-stimulated RMCs, control RMCs treated with chymase responded with increased expression of TGF-β1, Smad 3 and fibrosis markers. These effects were reversed by chymostatin but not by losartan. The results indicate an important role for chymase in inducing fibrosis through TGF-β1 activation, parallel with Ang II effects.

Chymase inhibition protects diabetic rats from renal lesions

“…Mast cells are thought to be the main source of chymase; however, the present study failed to identify abundant mast cells in renal tissues by toluidine blue staining (data not shown). This result is consistent with the findings of a previous study, in which Cristovam et al ( 10 ) demonstrated that mast cells were absent in both control and diabetic kidneys, thus suggesting that chymase is synthesized by resident renal cells.…”

“…The expression levels of the chymase encoding gene, RMCP-1, were markedly enhanced in diabetic kidneys. A previous study demonstrated that the mRNA expression levels of chymase were upregulated in glucose-stimulated mesangial cells ( 10 ). Mast cells are thought to be the main source of chymase; however, the present study failed to identify abundant mast cells in renal tissues by toluidine blue staining (data not shown).…”

Mast cell chymase protects against renal fibrosis in murine unilateral ureteral obstruction

“…56 On the other hand, examination of long-term-induced remodeling changes in an asthma model showed disease-aggravating roles by MC. 57 Similarly, data using chymase inhibitors have reported profibrotic actions for example via the generation of profibrotic Ang II or TGF-b1 in renal [58][59][60] or pulmonary fibrotic disease models, [61][62][63] but other studies show that downstream substrates of chymase like the matrix metalloproteinases activated either directly 19 or indirectly via the degradation of tissue inhibitor of metalloproteinases 18 are able to alleviate fibrosis. 64,65 These results indicate that similar to the general action of mast cells, mast cell chymase can have different roles, which depends on multiple factors including for example the involved type of organ, the type of injury, the kinetics of fibrosis development and so forth.…”

Combination of Chymostatin and Aliskiren attenuates ER stress induced by lipid overload in kidney tubular cells

“…Specific synthetic chymase inhibitors attenuate Ang II production and alleviate renal fibrosis through inhibition of activation of TGF-β in animal models [ 26 ]. Chymostatin is a strong inhibitor of chymases and it can effectively inhibit Ang II production in the kidney [ 27 , 28 ] and ameliorate salt-dependent hypertension [ 29 ].…”