Targeting of Receptor for Advanced Glycation End Products Suppresses Cyst Growth in Polycystic Kidney Disease

Abstract

Background: Receptor of advanced glycation end product (RAGE) mediates not only proinflammatory signaling, but also stimulates cell proliferation and survival-related signaling. Results: Inhibiting RAGE resulted in slowed cyst growth in an autosomal dominant polycystic kidney disease (ADPKD) mouse model and improved renal function. Conclusion: RAGE inhibition is highly effective against cyst enlargement in vivo. Significance: RAGE signaling may play a role in cystogenesis and could be a new therapeutic target for PKD.

Soluble receptor for advanced glycation end products inhibits disease progression in autosomal dominant polycystic kidney disease by down-regulating cell proliferation

“…They were kept in a 12-hour light-dark cycle at 20°C and 50% humidity and provided with sterilized water and food. The PC2R mice were previously established as explained in our advanced study (14). The jck mice were kindly provided by Seoul National University Hospital, and intraperitoneal injection was performed on male jck mice 3 times a week for 3 weeks, starting from 64 days after birth.…”

“…Furthermore, mice injected with anti-RAGE adenovirus showed enhanced renal function as well as suppressed kidney enlargement (14,15). Here, we tried to demonstrate the effects of the soluble form of RAGE, the decoy that blocks the RAGE-ligand interaction, to inhibit the disease phenotypes through RAGE-mediated cell proliferating signals.…”

“…Alternatively, conditional knockout models using kidney‐specific cre recombinase systems are currently available, but such models still suffer from radical and severe progression with short life spans of less than a month (13). In addition, we recently established PC2R (Pkd2 knockout rescued with human PKD2 transgene) mice, which rescued Pkd2 lethality by the human PKD2 gene, showing PKD phenotypes with a slightly‐longer life span compared with the conditional mice targeting Pkd1 or Pkd2 (14). Other models are spontaneous hereditary models produced by the modification of genes that are not always orthologous to human PKD genes.…”

AGEs–RAGE overexpression in a patient with smoking-related idiopathic nodular glomerulosclerosis

“…Advanced glycation end products (AGEs) are heterogeneous and complicated compounds formed by a non-enzymatic reaction between reduced sugar and amino acid of proteins, lipids, and DNAs [2,3]. Several basic and clinical studies have implicated AGEs and their receptor (RAGE) in the progression of not only diabetic nephropathy, but also obesity-related glomerulosclerosis, amyloidosis, and polycystic kidney disease [4][5][6][7]. On the other hand, smoking itself produces free radicals that are capable of inducing oxidative stress in several organs, which stimulates the formation of AGEs such as N-carboxymethyl lysine (CML).…”

Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways

“…Furthermore, it is well documented that RAGE is an inverse marker in CKD patients [ 17 ], thus inhibition of RAGE constituting a possible strategy for the treatment of CKD [ 18 , 19 ]. Soluble RAGE (sRAGE), which possesses the RAGE ligand binding positions but lacks the cytoplasmic and transmembrane domains, secretes out of the cells and acts as decoys to prevent RAGE signal transduction directly [ 20 ].…”