Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by deficiency of polycystin-1 (PC1) or polycystin-2 (PC2). Altered autophagy has recently been implicated in ADPKD progression, but its exact regulation by PC1 and PC2 remains unclear. We therefore investigated cell death and survival during nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 (PC1KO) or PC2 (PC2KO), and human urine-derived proximal tubular epithelial cells (PTEC) from early-stage ADPKD patients with PC1 mutations versus healthy individuals. Basal autophagy was enhanced in PC1-deficient cells. Similarly, following starvation, autophagy was enhanced and cell death reduced when PC1 was reduced. Autophagy inhibition reduced cell death resistance in PC1KO mIMCDs to the WT level, implying that PC1 promotes autophagic cell survival. Although PC2 expression was increased in PC1KO mIMCDs, PC2 knockdown did not result in reduced autophagy. PC2KO mIMCDs displayed lower basal autophagy, but more autophagy and less cell death following chronic starvation. This could be reversed by overexpression of PC1 in PC2KO. Together, these findings indicate that PC1 levels are partially coupled to PC2 expression, and determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common cystic kidney disease with a prevalence of ca. 1 in 1000–4000 [1]
This was supported by a stronger decline in confluence (Figure 1D), as well as more Cytotox-Greenpositive signals (Figure 1E) in WT mouse inner medullary collecting duct cells (mIMCDs) compared to PC1 knockout (PC1KO)
The elevation of cell death in WT mIMCDs compared to PC1KO was confirmed with Trypan Blue (Figure 1F), and was associated with the reduced levels of cleaved Caspase-3 in PC1KO mIMCDs (Figure 1G)
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common cystic kidney disease with a prevalence of ca. 1 in 1000–4000 [1]. ADPKD is paucisymptomatic until the 3rd–4th decade of life, (micro)cysts and symptoms are known to develop in children and even in utero [2]. It represents the fourth most common cause of kidney failure [3] and dialysis and transplantation remain the ultimate therapy. Renal cysts mostly develop due to mutations in PKD1 Mutations in PKD1 generally lead to a faster disease progression with kidney failure at a younger age compared to PKD2 [7]. Loss of function of PC1 and/or PC2 in animal cell lines leads to reduced intracellular Ca2+ signaling, increased mTOR activity, increased cAMP levels and increased proliferation [11]
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