**Acknowledgements**

and CCr was subsequently increased by the 10 and 30 mg/kg treatments in Thy-1 rats. In addition, ACR was also slightly decreased in a dose-dependent manner. Previous studies demonstrated that ACR is the most important index in GN and accurately assesses the progression of kidney injury [18, 24]. Therefore, we consider that the CCr and ACR to be more sensitive than plasma and/or serum creatinine. On the other hand, no significant change was observed in blood coagulation tests such as PT, APTT, TTO, and HPT. Based on results, AMT suppressed glomerular mesangial cell proliferation and the progression of glomerular disease in Thy-1 GN rats at a non-toxic dose. Recently, warfarin-related nephropathy (WRN) has been reported in patients with and without chronic kidney disease (CKD) [38, 39]. Clinical studies showed that mortality rates in 1 year were higher in WRN patients than in other patients. This result coincides with previous findings of increased mortality rates in warfarin-treated chronic hemodialysis patients [40, 41]. However, the increased mortality rate associated with WRN is related to the complications of diabetes, hypertension, cardiovascular disease, etc., and the mechanisms and risks of WRN currently remain unclear. Warfarin is a widely used anticoagulant for thrombotic complications and increases mortality rates in CKD patients. Further studies are necessary to assess how these complications are related to the mechanisms and

GN is a major process of end-stage renal disease (ESRD) along with diabetes and hypertension [42]. However, there are no appropriate therapeutic treatments for GN. In therapy for GN, steroids are widely used as anti-inflammation drugs for patients, particularly those with IgA nephropathy, which is typical mesangial proliferative GN [43, 44]. As steroids reduce proteinuria, they prevent the progression of kidney failure. However, extensive and severe side effects concerning the immune, circulating, and metabolic systems have been reported in patients with steroid therapy [45, 46]. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely treated for kidney disease in patients with diabetes and hypertension [47–49]. ACE inhibitors and ARBs control blood pressure by inhibiting the production of angiotensin II or preventing it from binding to angiotensin II receptors in the renin-angiotensin system, and, thus, reduce hypertension. In addition, nonclinical and clinical studies have demonstrated that ACE inhibitors and ARBs decrease proteinuria and prevent kidney failure [47, 50, 51]. In Thy-1 GN rats, treatments with ACE inhibitors or ARBs were found to inhibit increases in blood pressure and proteinuria, and subsequently the decline in renal function [52]. Persistent hypertension and glomerular hypertension may stretch the glomerular capillary wall, and result in endothelial damage and glomerular sclerosis, followed by a rise in protein glomerular filtration [53]. Schmieder [54] and Mochizuki et al. [55] reported that these compounds inhibited the kidney-specific reninangiotensin aldosterone system and prevented end-organ damage in the kidney beyond these antihypertensive effects. On the other hand, the VKOR inhibitor, AMT, prevents mesangial cell proliferation in the kidneys and suppresses the progression of GN. Unfortunately, AMT is not as effective by oral administration due to its low bioavailability. If improvements are archived in the biological stability of AMT, which has unique pharmacokinetic properties and is distributed to the kidney at a higher concentration than to the liver, VKOR inhibitors may be useful for the treatment for GN, particularly in combination with existing medications such as

risks [41].

304 Vitamin K2 - Vital for Health and Wellbeing

ACE inhibitors or ARBs.

Reprinted with permission from the Japanese Society of Veterinary Science (The Journal of Veterinary Medical Science, 2012; 74(7): 863–869) and John Wiley & Sons Inc. (Journal of Applied Toxicology, 2008; 28(4): 524–529).
