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Background/aims: We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model., Methods: In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy., Results: CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro., Conclusion: Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.

To evaluate the protecting effect of camostat mesylate, N,N-dimethylcarbamoylmethyl-p-(p-guanidinobenzoyloxy)phenylacetate methanesulfonate, one of the synthetic trypsin inhibitors, on diabetic nephropathy, urinary albumin excretion was measured in streptozotocin-induced (50 mg/kg, i.p.) diabetic rats treated with oral camostat mesylate for 12 weeks. The rats were divided into three groups: (1) nondiabetic control rats; (2) diabetic rats, and (3) diabetic rats received rat chow containing 0.1% camostat mesylate (PI rats). After induction of diabetes, the ratio of kidney weight to body weight and urinary albumin excretion (UAE) were significantly increased. However, the ratio of kidney weight to body weight in PI rats was significantly lower than that in diabetic rats, and UAE in PI rats was also significantly lower than that in diabetic rats at 4, 8 and 12 weeks. Kidney tissue insulin-like growth factor I (IGF-I) contents were significantly reduced in diabetic rats, and there were no significant differences in kidney tissue IGF-I contents between diabetic and PI rats. These results suggest that camostat mesylate reduces the UAE probably through an inhibitory effect on initial diabetic renal hypertrophy and that camostat mesylate is available for diabetic nephropathy.

A four-year-old male with steroid refractory nephrotic syndrome was found to have diffuse deposition of alpha 2-macroglobulin (alpha 2M) in the glomeruli which showed diffuse mesangial proliferation and partial hyalinization by light microscopy. Camostat mesylate, a commercially available synthetic proteinase inhibitor, led to biochemical and clinical improvement. Twenty-two patients with 7 biopsy-proven renal diseases did not have any deposition of alpha 2M in their kidney tissue. Though the pathogenetic mechanism is unknown, this is probably the first report of the deposition of alpha 2M in renal tissue.