Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress

Abstract

Although autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple kidney cysts, the most frequent cause of death in ADPKD patients is cardiovascular disease. ADPKD is linked to mutations in pkd1 or pkd2, the genes that encode for the proteins polycystin 1 and polycystin 2 (PC1 and PC2, respectively). The cardiovascular complications have been assumed to be a consequence of renal hypertension and activation of renin/angiotensin/aldosterone (RAAS) pathway. However, the expression of PC1 and PC2 in cardiac tissue suggests additional direct effects of these proteins on cardiac function. We previously reported that zebrafish lacking PC2 develop heart failure, and that heterozygous Pkd2+/− mice are hypersensitive to acute β-adrenergic receptor (βAR) stimulation. Here we investigate the effect of cardiac stress (prolonged continuous βAR stimulus) on Pkd2+/− mice. After βAR stimulation for 7 days, wildtype (WT) mice had increased left ventricular mass and natriuretic peptide (ANP and BNP) mRNA levels. The WT mice also had upregulated levels of PC2 and chromogranin B (CGB, an upstream regulator of BNP). Conversely, Pkd2+/− mice had increased left ventricular mass, but natriuretic peptide and CGB expression levels remained constant. Reversal of the increased cardiac mass was observed in WT mice 3 days after cessation of the βAR stimulation, but not in Pkd2+/− mice. We suggest that cardiac stress leads to upregulation of the PC2-CGB-BNP signaling axis, and this pathway regulates the production of cardio-protective natriuretic peptides. The lack of a PC2-dependent cardio-protective function may contribute to the severity of cardiac dysfunction in Pkd2+/− mice and in ADPKD patients.

Polycystin 2 is increased in disease to protect against stress-induced cell death

“…Studies seeking to elucidate how the loss of PC2 affects the heart have shown that with increased age, decreased PC2 levels result in cardiac dysfunction independent of renal abnormalities 87 . Additionally, in agreement with our findings, PC2 levels are enhanced in cardiomyocytes with cardiac injury, and Pkd2 +/mice show a diminished capacity to recover from injury following the cessation of stress 36 . It has been suggested that the extrarenal manifestations seen in ADPKD patients are merely secondary effects caused by the main pathology of renal cysts.…”

“…Although the most striking symptom of ADPKD is the formation of bilateral renal cysts, the most common cause of death in ADPKD patients is a consequence of cardiac abnormalities 45,46 . Due to the expression of PC2 in cardiac tissue and the apparent importance of the polycystins in heart function, PC2 levels were examined in a murine model of cardiomyopathy and were found to be increased in isoproterenol (ISO)-treated hearts compared to healthy controls 36 . We observed that cellular stress was induced in the hearts of these ISO-treated mice as indicated by increased 4-HNE levels (Fig.…”

“…It is established that the gene encoding for PC2, Pkd2, is differentially expressed during animal development to coordinate left-right axis determination in mice 32,33 and zebrafish 34 . However, despite reports of altered PC2 expression in pathological states 31,[35][36][37] , the conditions under which PC2 levels are regulated after development and into adulthood remain incompletely understood. Furthermore, how transcriptionally-regulated changes in PC2 levels influence the cellular response to stress remains unexplored.…”

Oxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression?

“…The underlying proteins in ADPKD, PC1 and PC2, are both membrane-bound glycoproteins and a subfamily of transient receptor potential (TRP) channels. Both proteins are present in the plasma membranes of the primary cilia of endothelial cells of all major vessels, where they form a heterodimeric molecular complex via their C-terminal chains [21,22]. PC1 can also be found in the plasma membranes at focal adhesion, desmosomes, and adherens junction sites, whereas PC2 is also located in the endoplasmic reticulum [23].…”

“…Mutations of PKD1 or PKD2 can lead to lower cytoplasmic Ca 2+ concentrations, which in turn causes an increase in adenylyl cyclase-6 activity and a decreased phosphodiesterase activity, leading to an increased cAMP abundance [21]. Alterations in the Ca 2+ homeostasis seem to have a role in the cardiovascular pathogenesis of ADPKD, since these alterations display changes in Ca 2+ signaling with reduced total intracellular and sarcoplasmic reticulum Ca 2+ levels [22].…”