Effect of the Novel Compound SMTP-27 in a Mouse Model of Diabetic Kidney Disease

Objective Diabetic kidney disease (DKD) is the most common complication of diabetes mellitus and one of the primary causes of end‐stage renal disease in many countries. Although several candidate substances have shown efficacy against DKD, no effective clinical treatment methods have been established for preventing the progression of DKD. It was recently noted that the occurrence of oxidative stress, one of the contributors to the pathogenesis of DKD, is closely related to inflammatory cell mobilization, a process that increases inflammation by inducing the production of cytokines such as interleukin‐1β and tumor necrosis factor‐α. The present study aimed to evaluate the effect of Stachybotrys microspora triprenyl phenol‐27 (SMTP‐27), which is reported to have an anti‐inflammatory effect, in a mouse model of DKD. Methods The right kidneys of male type 2 diabetic db/db mice (6 weeks) were removed through small flank incisions under isoflurane anesthesia to induce DKD. Male C57BL/6J mice of the same age, subjected to the same surgery, were used as the control group. DKD mice are randomly assigned to the vehicle‐treated group, SMTP‐27‐treated group (30 mg/kg), or metformin‐treated group (300 mg/kg). They were treated from six to sixteen weeks of age: SMTP‐27 injections were administered intraperitoneally once every two days, and metformin was orally administered daily. Urinary albumin (Ualb), serum creatinine (Scr), and creatinine clearance (Ccr) were measured to evaluate renal function. In addition, histological examination of an excised kidney was performed by hematoxylin‐eosin staining and periodic acid–Schiff staining to evaluate tubular regeneration and glomerular sclerosis. Results Ualb and Scr levels were significantly higher and Ccr levels were significantly lower in type 2 diabetic db/db mice than in C57BL/6J mice. Moreover, tubular regeneration and glomerular sclerosis were significantly higher in db/db mice than in C57BL/6J mice. In the type 2 diabetes model, metformin only improved Ualb with causing antihyperglycemic effects; in contrast, SMTP‐27 significantly improved Ualb, Scr, and Ccr without inducing antihyperglycemic effects. In addition, SMTP‐27 reduced tubular regeneration, whereas metformin did not. Neither drug reduced glomerular sclerosis. Conclusion Our results showed that SMTP‐27 improved DKD without inducing antihyperglycemic effects. Thus, SMTP‐27 is a potential novel therapeutic agent for the treatment of DKD. In future studies, we plan to investigate the mechanism of action of SMTP‐27 against DKD. Support or Funding Information This study was supported in part by the Japan Society for the Promotion of Science KAKENHI (Grant Number 18K14958, awarded to KS; Grant Number 26460346, awarded to KN). SMTP‐27 was generously donated by TMS Co., Ltd. (Tokyo, Japan).