Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of numerous kidney cysts. It is a progressive condition and symptoms usually worsen over time. It is one of the most prevalent hereditary causes of adult kidney failure and one of the most common genetic disorders worldwide. ADPKD affects 6–8% of Americans receiving dialysis. Cyst formation and organ enlargement in the kidney and other systems are two features of this multisystemic and progressive illness (e.g., liver, pancreas, spleen). Cysts may be visible via imaging (ultrasound or MRI) in children and in utero, although clinical signs typically start in the third to fourth decade of life. By the age of 60, up to 50% of ADPKD patients require kidney transplantation. The most prevalent known gene alterations in ADPKD are in the PKD1 and PKD2 genes; with less often occurring changes in the GANAB,DNAJB11, ALG9, and IFT140 genes. Because ADPKD does not skip a generation, unlike some hereditary disorders, it frequently affects many family members. Since ADPKD arises as a spontaneous (new) mutation, around 10% of those with the diagnosis have no family history of the condition. A person with ADPKD has a 50% risk of passing it on to each of their offspring..
Metabolic reprogramming is the term used to describe the reorganization of intracellular metabolic processes in response to a cell’s specific needs under pathological or physiological circumstances. A wide range of metabolic pathways have been reported reprogrammed in ADPKD, with most of these pathways engaged in central carbon metabolism. The cystogenesis in human and mouse PKD may be mediated by similar cellular mechanisms, and metabolic reprogramming is thought to be a key feature of the disease. In order to investigate the metabolic changes that the cystic kidney experiences as the disease progresses, researchers from the University of Colorado, Dr. Katharina Hopp, Dr. Emily Kleczko, Dr. Berenice Gitomer, Dr. Michel Chonchol, Dr. Jost Klawitter, Dr. Uwe Christians, and Dr. Jelena Klawitter conducted targeted metabolomics studies in kidneys of an orthologous mouse model of PKD (Pkd1RC/RC). Using the Kyoto Encyclopedia of Genes and Genomes pathway database, the researchers found several biologically significant metabolic pathways that were altered at early stages of this disease (in 3-month-old Pkd1RC/RC mice). The two metabolic pathways with the highest representation were arginine biosynthesis and metabolism and tryptophan and phenylalanine metabolism. Their findings are published in the American Journal of Physiology-Renal Physiology.
The research team found that the arginine biosynthesis pathway was differentially regulated in kidney tissues of 3-month-old Pkd1RC/RC mice. Increased arginase-mediated arginine metabolism led to elevated citrulline and ornithine concentrations. At 9 month, however, ornithine decarboxylation of ornithine strongly increased (via ornithine decarboxylase), resulting in declining ornithine levels and a more than threefold increase in the production of the polyamines putrescine and spermidine. Between 3 and 6 months, higher arginase activity and increased kidney levels of citrulline and ornithine persisted in Pkd1RC/RC mice. They further observed dysregulation of the methionine/homocysteine pathway at later stages of PKD, with noticeably higher levels of SAH, SAM, and homocysteine in 6 and 9 months old Pkd1RC/RC mice compared to age-matched wildtype animals for methionine or its oxidized counterpart, methionine sulfoxide. In the PKD animal model, these metabolites increase as kidney function diminishes with age, consistent with poorer renal function resulting in less kidney clearance of these metabolites. Lastly, the research team identified reprogramming of the tryptophan metabolism pathway within PKD kidneys compared to controls. This finding is of importance in two ways. First, the tryptophan metabolites, kynurenine and kynurenic acid which were markedly increased in Pkd1RC/RC mice as disease progresses, are known modulators of immune cell function. Interestingly, the immune cells impacted by these metabolites have been identified to drive kidney cysts growth. Secondly, enrichment of kynurenine and kynurenic acid associated with decreased levels of the tryptophan end product nicotinamide. Supplementation with nicotinic acid, a derivative of nicotinamide, has been shown to slow disease in mouse PKD models.
In conclusion, understanding the metabolic pathways of PKD should be considered for future clinical trials and personalized medicine. Dr. Katharina Hopp and colleagues validated previously reported findings and discovered new metabolic indicators and routes of PKD progression that may be useful for diagnosing and keeping track of patients’ cystic kidney disease. They also highlighted understudied pathomechanisms and suggested new targets for novel therapeutic strategies that merit further research.
Hopp K, Kleczko EK, Gitomer BY, Chonchol M, Klawitter J, Christians U, Klawitter J. Metabolic reprogramming in a slowly developing orthologous model of polycystic kidney disease. American Journal of Physiology-Renal Physiology. 2022 Feb 15.