In renal cell carcinoma (RCC), decreased expression of arginosuccinate synthase (ASS1) results in arginine auxotrophy; therefore, arginine deprivation has been proposed as a potential therapy. Now, Robert Weiss and colleagues report that arginine auxotrophy is also a feature of autosomal dominant polycystic kidney disease (ADPKD).
The researchers found that ASS1 is predominantly expressed in the proximal tubules in healthy human kidneys. In patients with ADPKD, ASS1 expression is maintained in non-atrophic proximal tubules but is reduced or absent in atrophic tubules. In RCC, ASS1 expression is reduced owing to promoter methylation; however, the ASS1 promoter was not methylated in the ADPKD samples. The researchers suggest that reduced ASS1 expression in ADPKD is the result of loss of proximal tubule cells owing to tissue atrophy.
Under conditions of arginine depletion, the proliferation and viability of Pkd1-/- cell lines was reduced compared to wild-type cells. In addition, using in vitro and ex vivo cyst assays, the researchers showed that lowering the concentration of arginine in the culture media reduces cystogenesis in a dose-dependent manner. “Glucose and glutamine reprogramming have previously been described in PKD, but our study is the first to describe arginine reprogramming,” notes Weiss.
Metabolomics analyses showed that arginine depletion mostly affected the glutamine and proline pathways and led to increased glutamine levels in wild type and Pkd1-/- cell lines. Moreover, when arginine deiminase (ADI) was used to deplete arginine in cell cultures, Pkd1-/- cells produced more glutamate than did wild-type cells. Based on these findings, the researchers suggest that arginine deficiency could lead to glutamine addiction in PKD.
“Decreasing circulating arginine levels is likely to affect cyst production but not normal tissues, as the latter can produce their own arginine,” says Weiss. “We foresee a trial of dietary arginine depletion and possibly ADI therapy in patients with ADPKD.”
Trott, J. F. et al. Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis. Am. J. Physiol. Renal Physiol. https://doi.org/10.1152/ajprenal.00025.2018 (2018)
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Wang, M. Arginine auxotrophy in PKD. Nat Rev Nephrol 14, 721 (2018). https://doi.org/10.1038/s41581-018-0076-5