Candesartan Cilexetil Restores Renal Endothelial Function Through Modulation of the ADMA-DDAH-eNOS Pathway in...

Renal dysfunction is a frequent and life-threatening complication of advanced cirrhosis and is particularly common in acute-on-chronic liver failure (ACLF), where it is associated with high mortality and poor clinical outcomes. This study aimed to (1) elucidate the role of the renal asymmetric dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-endothelial nitric oxide synthase (eNOS) axis in cirrhosis ± superimposed inflammation (mimicking ACLF) with renal dysfunction, and (2) evaluate the effects of CC on this pathway.

Male Wistar rats were administered carbon tetrachloride (15% v/v in corn oil, 0.5 mL/kg, twice weekly for 14 weeks) to induce cirrhosis with renal dysfunction. After 14 weeks, rats were randomized to receive CC (8 mg/kg orally for 2 weeks) before an acute lipopolysaccharide (LPS) challenge. All animals were sacrificed at week 16.

CCl₄-induced cirrhotic rats showed decreased mean arterial pressure (MAP), renal blood flow (RBF), and increased renal vascular resistance (RVR), and elevated kidney injury markers neutrophil gelatinase-associated lipocalin, blood urea nitrogen , and kidney injury molecule-1 along with heightened renal inflammation. Acute LPS administration further exacerbated these abnormalities. CC treatment markedly reduced renal injury and inflammatory markers in cirrhotic ± LPS-challenged rats, although MAP, RBF, and RVR remained unchanged. In ACLF rats with renal dysfunction, CC significantly lowered renal ADMA levels and increased phosphorylated eNOS and DDAH-1 expression, while DDAH-2 expression decreased. CC also restored renal nitric oxide (NO) levels, enhanced antioxidant enzyme activity, and reduced oxidative stress.

This study provides the first evidence that CC enhances renal NO bioavailability by upregulating DDAH-1 and eNOS expression and reducing ADMA accumulation, thereby improving renal endothelial function in cirrhosis with renal dysfunction. Targeting DDAH-1-mediated NO restoration may represent a promising therapeutic strategy for managing renal dysfunction in cirrhosis.