P2Y2R contributes to the development of diabetic nephropathy by inhibiting autophagy response

Abstract

Objective Diabetic nephropathy (DN) is one of the most common complications of diabetes and a critical risk factor for developing end-stage renal disease. Activation of purinergic receptors, including P2Y2R has been associated with the pathogenesis of renal diseases, such as polycystic kidney and glomerulonephritis. However, the role of P2Y2R and its precise mechanisms in DN remain unknown. We hypothesised that P2Y2R deficiency may play a protective role in DN by modulating the autophagy signalling pathway. Methods We used a mouse model of DN by combining a treatment of high-fat diet and streptozotocin after unilateral nephrectomy in wild-type or P2Y2R knockout mice. We measured renal functional parameter in plasma, examined renal histology, and analysed expression of autophagy regulatory proteins. Results Hyperglycaemia and ATP release were induced in wild type-DN mice and positively correlated with renal dysfunction. Conversely, P2Y2R knockout markedly attenuates albuminuria, podocyte loss, development of glomerulopathy, renal tubular injury, apoptosis and interstitial fibrosis induced by DN. These protective effects were associated with inhibition of AKT-mediated FOXO3a (forkhead box O3a) phosphorylation and induction of FOXO3a-induced autophagy gene transcription. Furthermore, inhibitory phosphorylation of ULK-1 was decreased, and the downstream Beclin-1 autophagy signalling was activated in P2Y2R deficiency. Increased SIRT-1 (sirtuin-1) and FOXO3a expression in P2Y2R deficiency also enhanced autophagy response, thereby ameliorating renal dysfunction in DN. Conclusions P2Y2R contributes to the pathogenesis of DN by impairing autophagy and serves as a therapeutic target for treating DN.

A novel palmitic acid hydroxy stearic acid (5‐PAHSA) plays a neuroprotective role by inhibiting phosphorylation of the m‐TOR‐ULK1 pathway and regulating autophagy

“…35 Other research has shown that the phosphorylation of ULK-1 was also reduced when autophagy was enhanced in diabetic nephropathy. 36 In the present study, we found that the administration of 5-PAHSA reduced the phosphorylation of m-TOR in both PC12 cells under diabetic condition and DB/DB mice. progression of AD and extend life span in transgenic mouse models of AD.…”

Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation

“…To assess the effect of geniposide on tubular damage, the expression of these biomarkers was evaluated by real-time PCR analysis. Consistent with our previous findings [28], the mRNA levels of KIM-1 and NGAL were significantly upregulated in DN mice compared to control, but reduced by geniposide treatment (Figure 2A). The protective effect of geniposide was further confirmed by PAS staining; DN mice showed a significant increase of tubulo-interstitial damage including tubular dilatation, loss of brush borders, necrosis and extracellular accumulation, which was reduced by geniposide treatment ( Figure 2B, damaged tubules are indicated by black arrows).…”

“…Renal histological abnormalities were assessed semi-quantitatively as previously described [28]. Briefly, after PAS staining, the severity of the glomerular injury was evaluated in randomly selected fields at 400× magnification and graded as follows: grade 0 = normal, grade 1 = <25%, grade 2 = 25-50%, grade 3 = 50-75% and grade 4 = 75-100% of segmental lesions.…”

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

“…Huang et al identified KCa3.1 (calcium-activated K+ channel) involved in renal tubular autophagy dysfunction through PI3K/Akt/mTOR signaling pathway in DKD (94). Theodomir et al confirmed that P2Y2R deficiency increased the expression of sirtuin-1 and FOXO3a, which enhanced autophagy and improved renal insufficiency in DKD (95). In addition, Yang et al found that Smad3, the downstream transcription factor activated by TGFβ (transforming growth factor β), suppressed lysosome biogenesis in a TFEB-dependent manner (96).…”