Cinacalcet-mediated activation of the CaMKKβ-LKB1-AMPK pathway attenuates diabetic nephropathy in db/db mice by modulation of apoptosis and autophagy

• Published in: Cell death & disease 2018-02, Vol.9 (3), p.270-20, Article 270
• Main Authors: Lim, Ji Hee, Kim, Hyung Wook, Kim, Min Young, Kim, Tae Woo, Kim, Eun Nim, Kim, Yaeni, Chung, Sungjin, Kim, Young Soo, Choi, Bum Soon, Kim, Yong-Soo, Chang, Yoon Sik, Kim, Hye Won, Park, Cheol Whee
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/51; 13/89; 14/19; 14/28; 64/60; 82/80; Albuminuria - enzymology; Albuminuria - pathology; Albuminuria - prevention & control; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Bcl-2 protein; Beta cells; Biochemistry; Biomedical and Life Sciences; Blood levels; Ca2+/calmodulin-dependent protein kinase; Calcium (blood); Calcium (intracellular); Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Calmodulin; Cell Biology; Cell Culture; Cells, Cultured; Cinacalcet - pharmacology; Diabetes; Diabetes mellitus; Diabetic Nephropathies - enzymology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - pathology; Diabetic Nephropathies - prevention & control; Diabetic nephropathy; Disease Models, Animal; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelial Cells - pathology; Enzyme Activation; Homeostasis; Humans; Immunology; Intracellular; Intracellular signalling; Kidney Glomerulus - drug effects; Kidney Glomerulus - enzymology; Kidney Glomerulus - pathology; Kidneys; Kinases; Life Sciences; Liver; LKB1 protein; Lymphoma; Male; Mice, Inbred C57BL; Nephropathy; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Oxidative stress; Oxidative Stress - drug effects; Phagocytosis; Phosphorylation; Podocytes - drug effects; Podocytes - enzymology; Podocytes - pathology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Rodents; Signal Transduction
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0324-4

Apoptosis and autophagy are harmoniously regulated biological processes for maintaining tissue homeostasis. AMP-activated protein kinase (AMPK) functions as a metabolic sensor to coordinate cellular survival and function in various organs, including the kidney. We investigated the renoprotective effects of cinacalcet in high-glucose treated human glomerular endothelial cells (HGECs), murine podocytes and C57BLKS/J- db/db mice. In cultured HGECs and podocytes, cinacalcet decreased oxidative stress and apoptosis and increased autophagy that were attributed to the increment of intracellular Ca 2+ concentration and the phosphorylation of Ca 2+ /calmodulin-dependent protein kinase kinaseβ (CaMKKβ)-Liver kinase B1 (LKB1)-AMPK and their downstream signals including the phosphorylation of endothelial nitric oxide synthase (eNOS) and increases in superoxide dismutases and B cell leukemia/lymphoma 2/BCL-2-associated X protein expression. Interestingly, intracellular chelator BAPTA-AM reversed cinacalcet-induced CaMKKβ elevation and LKB1 phosphorylation. Cinacalcet reduced albuminuria without influencing either blood glucose or Ca 2+ concentration and ameliorated diabetes-induced renal damage, which were related to the increased expression of calcium-sensing receptor and the phosphorylation of CaMKKβ-LKB1. Subsequent activation of AMPK was followed by the activation of peroxisome proliferator-activated receptor γ coactivator-1α and phospho-Ser 1177 eNOS-nitric oxide, resulting in a decrease in apoptosis and oxidative stress as well as an increase in autophagy. Our results suggest that cinacalcet increases intracellular Ca 2+ followed by an activation of CaMKKβ-LKB1-AMPK signaling in GECs and podocytes in the kidney, which provides a novel therapeutic means for type 2 diabetic nephropathy by modulation of apoptosis and autophagy.