Targeting Glutamine Metabolism in Kidney Development and Polycystic Kidney Disease

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2018-07-30

Authors

Flowers, Ebony Michelle

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Abstract

Polycystic kidney disease is a hereditary disorder characterized by the progressive manifestation of numerous fluid-filled sacs, known as cysts, within the renal epithelia. The enlargement of the cysts causes the gradual replacement of normal kidney parenchyma which leads to impairment of renal function, and ultimately, renal failure. While the primary causes of PKD are genetic mutations in one of the polycystins that encode the PKD1 and PKD2 proteins, the age of onset and severity of PKD cases greatly varies, suggesting other genes/processes are involved. Lkb1 is a serine-threonine kinase involved in the regulation of several molecular processes including cellular polarity, autophagy, mTOR signaling, and energetic stress response, all of which are dysregulated in PKD. We generated mice lacking Lkb1 in developing kidney epithelia to establish which of these processes contributed to cyst formation and progression in the absence of Lkb1. Surprisingly, Lkb1 mutant mice showed no defects in renal tubule development or maintenance. However, later studies revealed the co-ablation Lkb1 along with Tsc1, a gene known to play a role in human PKD, within the developing renal epithelia prompted a drastic acceleration in the timing, number, and size of cyst formation. We utilized in vitro cell culture coupled with ex vivo culture of embryonic kidneys with defined media allowed us to determine which metabolic pathways were affected by the deficit of Lkb1. Our results revealed that Lkb1 mutant cells and embryonic kidneys require glutamine for growth while wild-type cells and kidneys did not. Subsequent studies demonstrated that Pkd1 embryonic kidneys phenocopied Lkb1 mutant kidneys in respect to their reliance on glutamine for growth. Further investigation into defining which metabolic enzymes/pathways are regulated in normal kidney development and how the absence of Lkb1 or Pkd1 alters these metabolic processes will allow us to gain a greater understanding of the role of metabolism in PKD and potentially lead to t the development of therapeutics to reduce cyst number and/or size.

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