Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates.

Keywords: Cystic fibrosis; Hedgehog pathway; JAK2 protein; MAP kinase signaling system; PPAR gamma; Platelet endothelial cell adhesion molecule-1; Polycystin-1.

Fig. 1

Illustration of the hedgehog pathway. Hh: Hedgehog; SMO: Smoothened; PTCH: Patched; SuFu: Suppressor of Fused; Cos 2: Kinesin-like molecule costal 2; Ci: Cubitus interruptus; Fu: Serine/threonine protein kinase Fused. In the absence of the Hh ligand, PTCH receptor suppresses (shown by the dashed line) the G-protein coupled receptor (GPCR) named SMO. Hence, no further signaling cascade takes place which prevents cell proliferation. Hh signaling gets activated when a Hh ligand such as Sonic Hh binds to the PTCH. This ligand binding relieves the SMO, thereby it to modulate a complex known as hedgehog signaling complex (HSC). HSC is comprised of four different proteins namely SuFu, Fu, Cos2, and Ci. Here, in the figure, Ci is not shown in association with HSC. In the absence of Hh ligand, Cos2-Fu-Ci complex interacts with the C-tail of SMO which leads to the active form of Ci (Ci-A) that is responsible for the activation of target genes, leading to cellular processes like cell proliferation, and differentiation. In the absence of the Hh ligand, SuFu-Ci and Cos2-Fu-Ci complexes promote the repressor form of Ci (Ci-R), thereby preventing it to activate the target genes (Jia et al. 2015)

Fig. 2

Pictorial representation of the role of intracellular calcium in the pathophysiology of ADPKD. ADPKD: Autosomal dominant polycystic kidney disease; PI3K: Phosphatidylinositol-3-kinase. In a normal kidney epithelial cell, there is an increased level of intracellular calcium due to the proper functioning of polycystin-2 at the basolateral membrane and endoplasmic reticulum (not shown in the figure) along with other calcium ion channels. Increased calcium leads to the activation of PI3K that further activates the Akt. Akt leads to the inhibition of the proliferative factor; B-Raf and therefore abate the activation of other factors of Ras/Raf/MEK/ERK pathway (shown by the dashed line). In a renal epithelial cell with mutated polycystin-2, there is a low intracellular calcium level due to which B-Raf cannot get inhibited by the decreased formation of Akt that consequently leads to unabated cell proliferation (Mitobe et al. ; Li et al. 2016)

Fig. 3

The mechanism of STAT signaling by Polycystin-1. In autosomal dominant polycystic kidney disease (ADPKD), mutation of the PKD1 can lead to either the reduced or overexpression of polycystin-1. The over-expression of polycystin-1 (membrane-anchored) stimulates the activation of STAT1/3 by its phosphorylation of tyrosine. *Polycystin-1 binds to JAK2 that suggests polycystin-1 mediated regulation of JAK2 is attributable to the STAT1 activation. The other half of the figure is showing another model adopting which polycystin-1 regulates STAT proteins. In the ADPKD state, the 30 kilodalton (kDa) cytoplasmic (C) tail of polycystin-1 is released into the cytoplasm after cleavage and translocate to the nucleus where it interacts with the transcriptional co-activator P100 and STAT6 and co activates the STAT6. The remaining membrane-anchored portion (15 kDa) of polycystin-1 inhibits the STAT6 as it loses the ability to activate STAT6 (Ma et al. 2005)

Fig. 4

Illustration of the effects of polycystins dysfunctioning on EGFR and MAPK/ERK pathway. "Epidermal growth factor" (EGF) and "Insulin-like growth factor-1" (IGF-1) act as ligands for the epidermal growth factor receptor (EGFR). When gets activated by these ligands, dimerization of receptor is induced that leads to the activation of the tyrosine kinase activity of the receptor which further leads to the phosphorylation of tyrosine residues on each other (autophosphorylation) to form phosphotyrosine (shown by letter, 't'). The “growth factor receptor-bound protein-2” (GRB2) is an adaptor protein that helps to transduce the signals from EGFR to "Rouss avian sarcoma" (RAS) protein. GRB2 binds to phosphotyrosine and SOS protein via its SH2 and SH3 domains, respectively. The GRB2/SOS complex now activates the RAS. RAS in turn activates the RAF (protein kinase activity of RAF gets activated) that phosphorylates the mitogen-activated protein kinase kinase (MEK). MEK phosphorylates the extracellular signal-regulated kinase (ERK); also known as mitogen-activated protein kinase (MAPK) which further phosphorylates several other proteins that regulate cell proliferation, and differentiation. Decreased polycystin-1 expression lowers the activation threshold of the MAPK/ ERK pathway by IGF-1 and increased EGF-induced inward currents in kidney epithelial cell lines are produced due to over-expression of polycystin-2; together lead cystogenesis (Ma et al. ; Parker et al. 2007)

Fig. 5

Different mechanisms through which pioglitazone confers its actions in ADPKD