cGMP-dependent protein kinase I promotes cell apoptosis through hyperactivation of death-associated protein kinase 2

cGMP-dependent protein kinase (PKG) is a multifunctional protein. Whether PKG plays a role in ischemia-reperfusion-induced kidney injury (IRI) is unknown. In this study, using an in vivo mouse model of renal IRI, we determined the effect of renal IRI on kidney PKG-I levels and also evaluated whether overexpression of PKG-I attenuates renal IRI. Our studies demonstrated that PKG-I levels (mRNA and protein) were significantly decreased in the kidney from mice undergoing renal IRI. Moreover, PKG-I transgenic mice had less renal IRI, showing improved renal function and less tubular damage compared with their wild-type littermates. Transgenic mice in the renal IRI group had decreased tubular cell apoptosis accompanied by decreased caspase 3 levels/activity and increased Bcl-2 and Bag-1 levels. In addition, transgenic mice undergoing renal IRI demonstrated reduced macrophage infiltration into the kidney and reduced production of inflammatory cytokines. In vitro studies showed that peritoneal macrophages isolated from transgenic mice had decreased migration compared with control macrophages. Taken together, these results suggest that PKG-I protects against renal IRI, at least in part through inhibiting inflammatory cell infiltration into the kidney, reducing kidney inflammation, and inhibiting tubular cell apoptosis.

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cDNA Cloning and Gene Expression of Human Type Iα cGMP-Dependent Protein Kinase

Hypertension ◽

10.1161/01.hyp.27.3.552 ◽

1996 ◽

Vol 27 (3) ◽

pp. 552-557 ◽

Cited By ~ 56

Author(s):

Naohisa Tamura ◽

Hiroshi Itoh ◽

Yoshihiro Ogawa ◽

Osamu Nakagawa ◽

Masaki Harada ◽

...

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Cdna Cloning ◽

Dependent Protein Kinase ◽

Human Type ◽

Cgmp Dependent Protein Kinase ◽

Dependent Protein

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The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia

International Journal of Molecular Sciences ◽

10.3390/ijms22010052 ◽

2020 ◽

Vol 22 (1) ◽

pp. 52

Author(s):

Mirja Koch ◽

Constanze Scheel ◽

Hongwei Ma ◽

Fan Yang ◽

Michael Stadlmeier ◽

...

Keyword(s):

Protein Kinase ◽

Mouse Model ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Cone Photoreceptor ◽

Photoreceptor Degeneration ◽

Dependent Protein Kinase ◽

Genetic Ablation ◽

Cgmp Dependent Protein Kinase ◽

Dependent Protein

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.

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