The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

Polycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases. Jared J. Grantham, M.D., has done more than any other individual to promote PKD research around the world. However, despite decades of investigation there is still no approved therapy for PKD in the United States. In May 2014, the University of Kansas Medical Center hosted a symposium in Kansas City honoring the occasion of Dr. Grantham''s retirement and invited all the awardees of the Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease to participate in a forward-thinking and interactive forum focused on future directions and innovations in PKD research. This article summarizes the contributions of the 12 Kaplan awardees and their vision for the future of PKD research.     

Serum thyroglobulin measurements with a high sensitivity enzyme-linked immunosorbent assay: is there a clinical benefit in patients with differentiated thyroid carcinoma?

Serial serum thyroglobulin (Tg) measurements with a highly sensitive enzyme-linked immunosorbent assay (ELISA; functional sensitivity 0.03 ng/mL) in 126 patients (Tg autoantibody negative) with treated differentiated thyroid cancer (DTC) are described. At the beginning of the retrospective study, all 126 patients were in remission and Tg was detectable by ELISA in 92 (73%; range, 0.03-0.8 ng/mL). Over the following 4-year period, Tg levels remained essentially unchanged (i.e., any increases were less than 2 times the Tg level at the start of the study) in 121 of 126 (96%) and all 121 patients remained well. In 5 patients, Tg levels increased to more than 2 times the starting Tg level over the study period and in 4 of these 5, there was recurrence of DTC. The fifth patient in this group remains well as evidenced by extensive diagnostic imaging, although his serum Tg level continues to increase and can be stimulated by thyrotropin (TSH). Our results suggest that serial measurements of low levels of Tg by ELISA in treated patients with DTC enable detection of recurrence (without using TSH stimulation) 6-12 months earlier than would have been possible using a conventional Tg immuno-radiometric assay (IRMA). A prospective study is now needed to confirm these observations.     

Inhibition of macrophage fatty acid β-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses

Aims/hypothesis

Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid β-oxidation (FAO) affects macrophage responses to SFA.

Methods

We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures.

Results

To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD.

Conclusions/interpretation

Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.