Cyclo-glycylproline (cGP) Ameliorates Kidney Failure in Mice with Adenine-Induced Kidney Failure and db/db Mice

Background: Chronic kidney disease (CKD) is a worldwide public health problem with increasing prevalence, poor outcomes and high cost. Progression of CKD leads to accumulation of uremic toxins such as indoxyl sulfate (IS), trimethlyamine-N-oxide (TMAO), and phenyl sulfate (PS), which further accelerates the progression of CKD and is involved in a variety of CKD-related complications. Therefore, the reduction of the accumulated uremic toxins is important for the protection against CKD. Methods: Cyclo-glycylproline (cGP) is a cyclic dipeptide containing a condensation bond between glycine and proline. C57BL6 mice were fed a diet containing 0.2% adenine for 6 weeks to create a renal failure model. After the mice were created, they were switched to a normal diet and a diet containing 0.001% cGP for 2 weeks. Blood, urine, and organ samples were collected after administration. Similarly, db/db mice, a diabetic model mouse, were administered a diet containing 0.0031% cGP for 6 weeks, and blood, urine, and organ samples were collected. Plasma creatinine levels and urinary toxins were measured using LCMS/MS. Fibrosis of the renal cortex was also analyzed using Image J. Results: In mice with adenine-induced renal failure, serum creatinine levels were significantly (p<0.05) lower in the renal failure (RF) + cGP-treated group than in the RF group, suggesting improved renal function. In addition, a comparison of the residual tubular area of the kidneys showed that the residual tubular area was significantly increased in the cGP-treated group (RF group: 43%, RF + cGP group: 62%). No reduction in urinary toxins was observed. Next, db/db mice treated with cGP for 6 weeks also had significantly lower plasma creatinine levels compared to the control group. In addition, a comparison between before and after cGP treatment showed that plasma PS levels were significantly reduced in addition to plasma creatinine levels after cGP treatment, suggesting that cGP may be a novel therapeutic agent for DKD, as we have reported PS as an aggravating factor in the onset and progression of diabetic kidney disease (DKD) in a previous study. Conclusion: It is suggested that oral administration of cGP may improve renal function in renal failure model mice and diabetes model mice.