https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Heidelberg Klinik für Herzchirurgie Heidelberg, Deutschland; 2University of Tours INSERM UMR-1100, „Centre d‘Étude des Pathologies Respiratoires“ Tours, Frankreich; 3Boehringer Ingelheim Pharma GmbH & Co KG Medicinal Chemistry Biberach a.d. Riss, Deutschland; 4Universitätsklinikum Heidelberg Zentrum für Kinder- und Jugendmedizin Heidelberg, Deutschland; 5Universitätsklinikum Heidelberg Endokrinologie, Diabetologie, Stoffwechselkrankheiten und Klinische Chemie Heidelberg, Deutschland
Background:
Polycystic kidney disease (PKD) is a genetic disorder that can present in either autosomal dominant or autosomal recessive forms. It is characterized by the development of large, fluid-filled cysts, which lead to renal dysfunction. In addition to cyst formation, patients with PKD may experience secondary hypertension and cardiovascular complications. Evidence suggests that inflammation plays a role in the progression of both PKD and endothelial dysfunction. During inflammation, neutrophils become activated and release pro-inflammatory neutrophil serine proteases (NSPs). Excessive proteolytic activity of NSPs can lead to tissue damage. To inhibit the activation of these NSPs during neutrophil maturation, we used the cathepsin C inhibitor BI-9740 (BI) (OpnMe/Boehringer Ingelheim) and hypothesized that its oral administration alleviates vascular dysfunction in a rat model of PKD.
Polycystic kidney disease (PKD) is a genetic disorder that can present in either autosomal dominant or autosomal recessive forms. It is characterized by the development of large, fluid-filled cysts, which lead to renal dysfunction. In addition to cyst formation, patients with PKD may experience secondary hypertension and cardiovascular complications. Evidence suggests that inflammation plays a role in the progression of both PKD and endothelial dysfunction. During inflammation, neutrophils become activated and release pro-inflammatory neutrophil serine proteases (NSPs). Excessive proteolytic activity of NSPs can lead to tissue damage. To inhibit the activation of these NSPs during neutrophil maturation, we used the cathepsin C inhibitor BI-9740 (BI) (OpnMe/Boehringer Ingelheim) and hypothesized that its oral administration alleviates vascular dysfunction in a rat model of PKD.
Method:
The PCK rat model, derived from Sprague-Dawley (SD) rats, develops both PKD and liver disease, making it a suitable model for autosomal recessive PKD. Nine-month-old male PCK and age-matched control SD rats were administered either a placebo or BI (20 mg/kg body weight) once daily for 12 days. On day 13, the thoracic aorta was harvested, prepared, and aortic rings were mounted in organ bath chambers for ex vivo measurement of vascular function.
The PCK rat model, derived from Sprague-Dawley (SD) rats, develops both PKD and liver disease, making it a suitable model for autosomal recessive PKD. Nine-month-old male PCK and age-matched control SD rats were administered either a placebo or BI (20 mg/kg body weight) once daily for 12 days. On day 13, the thoracic aorta was harvested, prepared, and aortic rings were mounted in organ bath chambers for ex vivo measurement of vascular function.
Results:
PCK+BI rats showed decreased serum creatinine and urea levels compared to the PCK rats (creatinine: 32±1 vs. 43±4 µmol/l, p<0.05; urea: 2981±198 vs. 3816±259 µmol/l, p<0.05). PCK rats’ body weight were significantly less than age-matched control SD rats (581±21 vs. 743±12g, p<0.05), and oral administration of BI for 12 days did not affect body weight compared to the placebo-treated animals (570±8 vs. 581±21g, p>0.05), a parameter used for safety assessment. The decreased maximum endothelium-dependent relaxation (Rmax) to acetylcholine at higher concentrations in the PCK rats compared to the controls was ameliorated by BI (SD: 79±1, PCK: 61±2, PCK+BI: 70±2%, p<0.05), indicating improved endothelial function. Additionally, maximum contractile responses to the alpha 1 adrenergic receptor phenylephrine were lower in the PCK-BI group compared to both the control and PCK groups (SD: 92±2%, PCK: 90±2%, PCK+BI: 78±3%, p<0.05). Although there was no difference in maximum endothelium-independent relaxation to sodium nitroprusside among the groups, BI treatment caused a leftward shift in the concentration-response curve compared to the PCK rats. The sensitivity to sodium nitroprusside, indicated by the pD2 value (the negative logarithm of EC50), was as follows: SD: 8.9±0.2, PCK: 8.4±0.1, PCK+BI: 9.6±0.3, p<0.05.
PCK+BI rats showed decreased serum creatinine and urea levels compared to the PCK rats (creatinine: 32±1 vs. 43±4 µmol/l, p<0.05; urea: 2981±198 vs. 3816±259 µmol/l, p<0.05). PCK rats’ body weight were significantly less than age-matched control SD rats (581±21 vs. 743±12g, p<0.05), and oral administration of BI for 12 days did not affect body weight compared to the placebo-treated animals (570±8 vs. 581±21g, p>0.05), a parameter used for safety assessment. The decreased maximum endothelium-dependent relaxation (Rmax) to acetylcholine at higher concentrations in the PCK rats compared to the controls was ameliorated by BI (SD: 79±1, PCK: 61±2, PCK+BI: 70±2%, p<0.05), indicating improved endothelial function. Additionally, maximum contractile responses to the alpha 1 adrenergic receptor phenylephrine were lower in the PCK-BI group compared to both the control and PCK groups (SD: 92±2%, PCK: 90±2%, PCK+BI: 78±3%, p<0.05). Although there was no difference in maximum endothelium-independent relaxation to sodium nitroprusside among the groups, BI treatment caused a leftward shift in the concentration-response curve compared to the PCK rats. The sensitivity to sodium nitroprusside, indicated by the pD2 value (the negative logarithm of EC50), was as follows: SD: 8.9±0.2, PCK: 8.4±0.1, PCK+BI: 9.6±0.3, p<0.05.
Conclusion:
These preliminary results suggest that pharmacological inhibition of the cysteine protease cathepsin C provides a protective effect on vascular function in a 9-month-old rat model of autosomal recessive PKD.
These preliminary results suggest that pharmacological inhibition of the cysteine protease cathepsin C provides a protective effect on vascular function in a 9-month-old rat model of autosomal recessive PKD.