CaMKII as a pathological mediator of ER stress, oxidative stress, and mitochondrial dysfunction in a murine model of nephronophthisis

Abstract

Polycystic kidney diseases (PKDs) are genetic diseases characterized by renal cyst formation with increased cell proliferation, apoptosis, and transition to a secretory phenotype at the expense of terminal differentiation. Despite recent progress in understanding PKD pathogenesis and the emergence of potential therapies, the key molecular mechanisms promoting cystogenesis are not well understood. Here, we demonstrate that mechanisms including endoplasmic reticulum stress, oxidative damage, and compromised mitochondrial function all contribute to nephronophthisis-associated PKD. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is emerging as a critical mediator of these cellular processes. Therefore, we reasoned that pharmacological targeting of CaMKII may translate into effective inhibition of PKD in jck mice. Our data demonstrate that CaMKII is activated within cystic kidney epithelia in jck mice. Blockade of CaMKII with a selective inhibitor results in effective inhibition of PKD in jck mice. Mechanistic experiments in vitro and in vivo demonstrated that CaMKII inhibition relieves endoplasmic reticulum stress and oxidative damage and improves mitochondrial integrity and membrane potential. Taken together, our data support CaMKII inhibition as a new and effective therapeutic avenue for the treatment of cystic diseases.

Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease

“…We found evidence of renal oxidative stress at a very early stage of PKD, reflected by increased renal immunoreactivity of 8-OHdG, that aggravated with disease progression. This is consistent with previous studies in rodent models of PKD that have shown significant increases in 8-OHdG expression in kidney cyst-lining cells [16,25]. Interestingly, we found that this increase in renal 8-OHdG levels was not limited to the cyst-lining TECs and was also present in non-cystic tubules, suggesting that the non-cystic parenchyma is also a contributor to renal oxidative stress.…”

Endoplasmic reticulum stress and calcium imbalance are involved in cadmium-induced lipid aberrancy in Saccharomyces cerevisiae

“…This result might suggest that cytosolic Ca 2+ was increased, and ER calcium reduced. Inhibition of CaMKII (calcium calmodulin kinase) reduced the ER stress, mitochondrial integrity, and membrane potential in murine cells (Bracken et al 2016). Previous studies also revealed that the ratio of phosphatidylcholine and phosphatidylethanolamine in membrane resulted in ER stress and Ca 2+ imbalance in mice hepatocytes (Fu et al 2011).…”

Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis

“…Our finding that mitochondrial dysfunction confers defects in cilium formation suggests that mutations in mitochondriaassociated genes could cause situs anomalies such as heterotaxy. Ciliopathy phenotypes are rare in mitochondriopathy patients, but have been reported in certain cases (30)(31)(32)(33)(34). Nevertheless, there is phenotypic overlap in symptomatology.…”