Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

Food Restriction Ameliorates the Development of Polycystic Kidney Disease

“…We further evaluated the glucose sensitivity of several cellular models of ADPKD. In contrast with recently published data, 4,19 we observed that mouse embryonic fibroblasts (MEFs) derived from at least two different mouse models of ADPKD and one human cell line derived from a patient with ADPKD, were not more sensitive to changes in glucose availability and did not have higher lactate production than WT cells ( The effect of glucose deprivation on apoptosis was also evaluated in these cells. While the percentage of apoptotic cells observed in Pkd1 MEFs and human PKD1 null cyst epithelial lining cells was slightly higher than the respective WT controls, no changes in apoptosis were observed in response to 48 hours of glucose starvation, as assessed by annexin V and terminal deoxynucleotidyl transferase-mediated digoxigenindeoxyuridine nick-end labeling (TUNEL) ( Figure 3E, del2/del2 cells exposed to varying glucose concentrations.…”

Apoptosis in Polycystic Kidney Disease: From Pathogenesis to Treatment

“…Overexpression of neutrophil gelatinase-associated lipocali (NGAL) mediated by adenovirus suppressed renal cyst growth in Pkd1 flox/-:Ksp-Cre mice, partially due to the induction of apoptosis of cystic epithelial cells by sequestration of intracellular iron and subsequent activation of Bim1 (54,127). In addition, as we described above, both SIRT1 inhibitors and the MIF inhibitor delayed cyst growth in Pkd1 knockout mice partially through induction of cystic epithelial cell death through the activation of p53 (57,58), whereas Smac-mimetics slowed cyst growth mostly though disruption of the TNF-α mediated pro-survival NF-κB signaling and then induction of cell death in cystic epithelium but not the non-cystic epithelial cells (53). These studies suggest that induction of cyst lining epithelial cell apoptosis, with or without a decrease in proliferation, can help to slow cyst growth in Pkd1 mutant animal models.…”

“…Furthermore, recent studies indicated that, although deletion of Pkd1 results in an incremental increase in cell proliferation in the Pkd1 conditional knockout Pkd1 flox/-:KspCre mice, Pkd1 flox/-Pkhd1-Cre mice and Pkd1 hypomorphic Pkd1 nl/nl mice, increased apoptosis was not a feature in kidneys from these mice as the TUNEL-positive nuclei are negligible and had no difference between cystic and non-cystic kidneys (53,54,57,87). This provided further evidence that apoptosis is not the primary factor of cystogenesis at least in Pkd1 knockout animals.…”

“…Whether apoptosis is changed in Pkd1 and Pkd2 knockout animal models is uncertain. Recent studies have indicated that induction of cyst lining epithelial cell apoptosis may delay renal cyst growth in Pkd1 knockout mouse models (53)(54)(55)(56)(57)(58). These studies suggest that the role of apoptosis in promotion or retardation of cyst growth in PKD could be disparate, depending on confounding factors such as animals compared to humans, early compared to late disease, tubules and interstitial cells compared to cystlining epithelial cells and different primary end-points to measure the levels of apoptosis (53).…”

“…For example, inhibition of SIRT1 with nicotinamide or EX-527 decreased cystic renal epithelial cell proliferation by inactivation of p-Rb, and induced its apoptosis by activating p53 in a Pkd1 conditional knockout mouse model (58). In addition, inhibition of macrophage migration inhibitory factor (MIF) with ISO-1 decreased cystic renal epithelial cell proliferation but increased apoptosis (57). However, the direct role that inducing apoptosis within proliferating cystic renal epithelium has in delaying cyst growth in ADPKD is not provided by these studies, since inhibiting cell proliferation may be the predominant effect.…”