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

Abstract

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.

Efficient genome editing of differentiated renal epithelial cells

“…Yet, the molecular function of the respective proteins, Polycystin-1 (PC1) and transient receptor potential channel Polycystin-2 (TRPP2), has remained elusive [2]. To demonstrate the versatility of our genome editing approach, we have established multiple novel cell lines for the study of ADPKD by introducing targeted mutations into PKD1 and PKD2 (Supplementary Table 1–4): (1) deletions of PKD genes (Fig.…”

Nephrology research—the past, present and future

“…The most notable progress in basic nephrology research has been in the field of polycystic kidney disease (PKD). 6 The onset, progression and severity of autosomal dominant polycystic kidney disease (ADPKD) is now known to be determined by the dosage and nature of mutations in PKD1 and PKD2; the genetic background of other cilia-associated modifier genes such as the autosomal recessive PKD gene PKHD1; as well as 'second hit' somatic mutations. Downstream mechanisms involving cilia motility, intracellular calcium and cyclic nucleotide signalling, cell cycle regulation and cross-talk between the epithelial cell and the cytoskeleton all contribute to cysto genesis.…”

“…Major advances in our understanding of the genetics of ADPKD as well as the discovery of signalling and metabolic pathways associated with cystogenesis point to many opportunities for novel pharmacologic development (Figure 3). 6 However, despite these promising advances in basic science over the past 10 years, with notable lines of translational research into vasopressin V2-receptor antagonism and inhibition of mammalian target of rapamycin, no clinical trial to date has resulted in FDA approval of a novel therapy for PKD. 40 Although the pathological pathways involved in ADPKD are complex and interact, which might aid the development of potential therapeutic approaches, the very nature of this intricate but delicate balance could also pose considerable challenges.…”

Serum Fas Ligand, Serum Myostatin and Urine TGF-β1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function

“…In adult mice with inactivated PKD1 gene showed, nephrotoxic injury led to increased proliferation of tubular epithelial cells and accelerated the formation of cysts [9]. Such observations suggest that the presence of abnormal polycystins, or reduced expression of the normal proteins, lead to renal cyst formation, but other mechanisms, such as kidney injury from ischemia-reperfusion or other nephrotoxic, paracrine or inflammatory factors that promote tubular damage initiation, activation of the apoptotic process, and increased cell proliferation, can accelerate cystogenesis [10]. Furthermore, polycystins are present not only in renal tubular cells, but also in the primary cilia of endothelial cells of renal microvasculature, where they function as flow sensors [11].…”