Lkb1 deficiency confers glutamine dependency in polycystic kidney disease

Ebony M. Flowers,Lauren Zacharias,Roy Zent,Jessica Sudderth,Glenda Mernaugh,Ralph J. DeBerardinis,Thomas J. Carroll

doi:10.1038/s41467-018-03036-y

Abstract

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth. Metabolomics analysis suggests that Lkb1 mutant kidneys require glutamine for non-essential amino acid and glutathione metabolism. Inhibition of glutamine metabolism in both Lkb1/Tsc1 and Pkd1 mutant mice significantly reduces cyst progression. Thus, we identify a role for Lkb1 in glutamine metabolism within the kidney epithelia and suggest that drugs targeting glutamine metabolism may help reduce cyst number and/or size in PKD.

Highlights

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys
PKD is similar to neoplastic disorders in that the formation and enlargement of cysts is largely due to increased cellular proliferation and growth, abnormal cell polarity, and altered cellular metabolism[1,2,3,4,5,6]
Lkb1/Stk[11] is a serine/threonine kinase that has been reported to regulate cell proliferation, polarity, mTOR activity, and energy metabolism[6,24,25,26,27,28], all of which are perturbed in PKD

Summary

Introduction

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Co-ablation of Lkb[1] and Tsc[1], an mTOR repressor, results in an early developing, aggressive form of PKD We find that both loss of Lkb[1] and loss of Pkd[1] render cells dependent on glutamine for growth. The age of onset and severity of progression varies greatly and can begin as early as childhood/adolescence This spectrum of individuals/ cases suggests that additional modifications from genetic, epigenetic, or environmental factors contribute to disease pathology and represent a prospective set of therapeutic targets to inhibit or slow cyst progression. Several classes of drugs have been identified as having potential benefit in autosomal dominant polycystic kidney disease in animal models Available treatments, such as Tolvaptan that alleviate cyst enlargement through the regulation of water and sodium transport, have systemic side effects that restrict usage[8,9]. Understanding how metabolism is (mis)regulated in PKD may lead to the development of therapeutics that can reduce increased cell proliferation, one of the principal drivers of PKD

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