Abstract
Our previous in vitro studies suggested that cyclic AMP (cAMP) signaling prevents adriamycin (ADR) and puromycin aminonucleoside (PAN)-induced apoptosis in podocytes. As cAMP is an important second messenger and plays a key role in cell proliferation, differentiation and cytoskeleton formation via protein kinase A (PKA) or exchange protein directly activated by cAMP (Epac) pathways, we sought to determine the role of PKA or Epac signaling in cAMP-mediated protection of podocytes. In the ADR nephrosis model, we found that forskolin, a selective activator of adenylate cyclase, attenuated albuminuria and improved the expression of podocyte marker WT-1. When podocytes were treated with pCPT-cAMP (a selective cAMP/PKA activator), PKA activation was increased in a time-dependent manner and prevented PAN-induced podocyte loss and caspase 3 activation, as well as a reduction in mitochondrial membrane potential. We found that PAN and ADR resulted in a decrease in Mfn1 expression and mitochondrial fission in podocytes. pCPT-cAMP restored Mfn1 expression in puromycin or ADR-treated podocytes and induced Drp1 phosphorylation, as well as mitochondrial fusion. Treating podocytes with arachidonic acid resulted in mitochondrial fission, podocyte loss and cleaved caspase 3 production. Arachidonic acid abolished the protective effects of pCPT-cAMP on PAN-treated podocytes. Mdivi, a mitochondrial division inhibitor, prevented PAN-induced cleaved caspase 3 production in podocytes. We conclude that activation of cAMP alleviated murine podocyte caused by ADR. PKA signaling resulted in mitochondrial fusion in podocytes, which at least partially mediated the effects of cAMP.
Highlights
Most glomerular diseases share the common features of proteinuria and effacement of podocyte foot processes [1]
Glomerular parietal epithelial cells or stem cells may differentiate into podocytes [6,7,8], a large amount of evidence suggests that podocyte loss including detachment or apoptosis leads to reduced podocyte number in the disease state [9,10,11]
We found that the TUNEL-positive podocyte number was inversely associated with the WT-1 positive cell number in the adriamycin (ADR) mouse model, indicating that apoptosis contributes, at least partially, to podocyte loss [12]
Summary
Most glomerular diseases share the common features of proteinuria and effacement of podocyte foot processes [1]. Recent studies have shown that podocyte injury is involved in the development of podocytopenia and glomerulosclerosis [2]. The first event initiating the process of glomerulosclerosis is podocyte loss [3,4]. Glomerular parietal epithelial cells or stem cells may differentiate into podocytes [6,7,8], a large amount of evidence suggests that podocyte loss including detachment or apoptosis leads to reduced podocyte number (podocytopenia) in the disease state [9,10,11]. We found that the TUNEL-positive podocyte number was inversely associated with the WT-1 positive cell number in the adriamycin (ADR) mouse model, indicating that apoptosis contributes, at least partially, to podocyte loss [12]
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