799-P: Nephroprotective Effects of a Novel Long-Acting GLP-1/GIP/GCG Triple Agonist, HM15275, in Preclinical Models of Acute and Chronic Kidney Diseases

Introduction & Objective: Obesity is associated with the risk of chronic kidney disease (CKD). Recently, potential benefits of incretin drugs on cardio- and renal-related outcomes were demonstrated. The aim of this study is to evaluate whether HM15275, which shows a potent anti-obesity effect with optimized GLP-1/GIP/GCG activity balance, also has a renal protective effect.

Methods: To investigate therapeutic effect on acute kidney injury, unilateral ureteral obstruction (UUO) mice were administered with HM15275, followed by determining the kidney structure and renal fibrosis. In angiotensin II (Ang II) mice, spontaneously hypertensive rats (SHR), and AMLN mice, renal fibrosis and function were determined after 2 ~ 16 weeks treatment. Human primary podocytes and renal proximal tubular epithelial cells (RPTEC) were used for in vitro mechanistic study. Tirzepatide (TZP) was used as comparative control.

Results: UUO-induced increased pro-col1α1 in the kidney was robustly attenuated by HM15275 (-35.3% vs. TZP; p<0.05). In Ang II mice, HM15275 treatment showed significantly less renal dysfunction (BUN, serum creatinine, and uACR). Similarly, elevated levels of renal pro-col1α1 were significantly attenuated by HM15275 (-40.3% vs. TZP; p<0.01). In SHRs, urinary albumin excretion (-76.5% vs. TZP; p<0.01) and uACR (-72.0% vs. TZP; p<0.01) were significantly improved by HM15275 treatment for 16 weeks. Consistently, improvement of gluomerulosclerosis was observed in AMLN mice. In mechanistic study, suppression of stress-induced apoptosis in podocytes and reduced expression of EMT markers in RPTEC well explain how HM15275 could provide renal protection effects in AKI and CKD models.

Conclusion: HM15275 improved renal damage and fibrosis more effectively than TZP. Considering the observation in podocytes and RPTEC, HM15275 might have direct nephroprotective effects in addition to the improvement of metabolic abnormalities.