#4542 L-Arginine-Nitric Oxide Molecular Pathway in Autosomal Dominant Polycystic Kidney Disease

Abstract

Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited, complex disease, cystogenesis and phenotypic changes in this disorder being not yet fully understood. Recently, arginine, important for renal cells metabolism, was proved to play an important role in ADPKD physiopathology (1). The inability of cells to recycle or synthesize intracellular arginine through the urea cycle is defined as arginine auxotrophy. Arginine auxotrophy in ADPKD induces cell hyperproliferation, and cysts formation (2). We aimed to explore L-Arginine (Arg) - Nitric Oxide (NO) molecular pathway in ADPKD, a multisystemic, arginine auxotrophe disease. Method We developed a prospective, case control study, in Carol Davila Clinical Hospital of Nephrology, Bucharest, Romania. The study included a group of 62 subjects with ADPKD (mean age -54.3years old, men:women 34:28, with 1A and 1B Mayo ADPKD risk classes) and a group of 37 healthy subjects, similar as sex, mean age. ADPKD diagnosis was based on familial history, clinical exam and CT or MRI scan. We excluded from the study subjects that presented cysts in other organs except the kidney, with eGFR<60mL/min/1.73mp, with history of hematuria, cysts infection, urinary tract infection, renal lithiasis, with unstable blood pressure and hypertensive treatment for less than 6 months; metabolic disorders (carbamoyl phosphate synthase 1 and N-acetyl glutamate synthase deficiencies, lack of ornithine transcarbamilase, hyperargininemia, phenylketonuria). Laboratory tests: serum level of arginine, enzymatic activity of arginase 2 (ARG-2) and nitric oxide inducible synthase (NOS-2), serum levels of stable metabolites of nitric oxide (nitrate, direct nitrite, total nitrite), endogenous inhibitors of nitric oxide synthesis (Asymmetric Dimethylarginine -ADMA, Symmetric Dimethylarginine SDMA). Results In ADPKD patients, the serum levels of arginine and of the stable metabolites of nitric oxide had statistically significant lower levels compared with control group (Table 1). The levels of the principal enzymes that metabolizes arginine – arginase 2 and nitric oxide inducible synthase, respectively the endogenous inhibitors of nitric oxide synthesis were statistically significant higher in ADPKD group when compared with control group (Table 1). The ARG2/Arg, NOS2/Arg, Nitrite/Arg, Nitrate/Arg, ADMA/Arg and SDMA/Arg ratios were statistically significant overexpressed in ADPKD group when compared with control group. Conclusion ADPKD is a metabolic kidney disease, auxotrophic for arginine. The metabolic ADPKD phenotype of renal cells with low risk of progression (1A and 1B Mayo) is defined by the alteration of L-Arginine-NO molecular pathway, the significant reduction of systemic arginine, moderately increased enzymatic activities of ARG2 and NOS2, the reduction of the synthesis and bioactivity of NO. Exploring arginine reprogramming and related molecular L-Arg-NO pathways disturbances could offer more information about ADPKD physiopathology.

The Role of the L-Arginine–Nitric Oxide Molecular Pathway in Autosomal Dominant Polycystic Kidney Disease

“…Arginine has many functions in human physiology and pathology. Many disorders mediated by arginine and its metabolites have been intensively studied recently [ 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. The equilibrium of arginine production in the human body by physiological adaption or by pharmacological therapies could be an efficient method for the prevention or treatment of L-arginine–NO pathway metabolic alteration-associated diseases [ 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”