TFP5-Mediated CDK5 Activity Inhibition Improves Diabetic Nephropathy via NGF/Sirt1 Regulating Axis

Abstract

Diabetic nephropathy (DN) is one of the leading causes of chronic kidney disease (CKD), during which hyperglycemia is composed of the major force for the deterioration to end-stage renal disease (ESRD). However, the underlying mechanism triggering the effect of hyperglycemia on DN is not very clear and the clinically available drug for hyperglycemia-induced DN is in need of urgent development. Here, we found that high glucose (HG) increased the activity of cyclin-dependent kinase 5 (CDK5) dependent on P35/25 and which upregulated the oxidative stress and apoptosis of mouse podocytes (MPC-5). TFP5, a 25-amino acid peptide inhibiting CDK5 activity, decreased the secretion of inflammation cytokines in serum and kidney, and effectively protected the kidney function in db/db mouse from hyperglycemia-induced kidney injuries. In addition, TFP5 treatment decreased HG-induced oxidative stress and cell apoptosis in MPC-5 cells and kidney tissue of db/db mouse. The principal component analysis (PCA) of RNA-seq data showed that MPC-5 cell cultured under HG, was well discriminated from that under low glucose (LG) conditions, indicating the profound influence of HG on the properties of podocytes. Furthermore, we found that HG significantly decreased the level of NGF and Sirt1, both of which correlated with CDK5 activity. Furthermore, knockdown of NGF was correlated with the decreased expression of Sirt1 while NGF overexpression leads to upregulated Sirt1 and decreased oxidative stress and apoptosis in MPC-5 cells, indicating the positive regulation between NGF and Sirt1 in podocytes. Finally, we found that K252a, an inhibitor of NGF treatment could undermine the protective role of TFP5 on hyperglycemia-induced DN in db/db mouse model. In conclusion, the CDK5-NGF/Sirt1 regulating axis may be the novel pathway to prevent DN progression and TFP5 may be a promising compound to improved hyperglycemia induced DN.

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“…CDK5's relevance extends beyond neurodegenerative diseases; for example, inhibiting its activity has shown promise in reducing facial inflammatory pain in mice (Hu et al, 2022). Investigating the CDK5–nerve growth factor/sirtuin 1 (NGF/SIRT‐1) regulatory axis pathway holds potential for the development of treatments for diabetic nephropathy (Cao et al, 2022). Furthermore, knockdown of CDK5 has been found to inhibit HIF‐1α expression (Chao et al, 2020).…”

TFP5 attenuates cyclin‐dependent kinase 5‐mediated islet β‐cell damage in diabetes

“…We have previously confirmed that TFP5 can effectively inhibit CDK5/P25 activity, and can reduce apoptosis in neurodegeneration experiments and HG‐stimulated neurons experiment, without affecting the physiological activities of CDK5/P35 and other CDKs (Amin et al, 2016; Binukumar et al, 2014; Shukla et al, 2013). In addition, we found that TFP5 regulates the nerve growth factor/sirtuin 1 axis by inhibiting the hyperactivity of CDK5/P25 in a diabetic nephropathy model, inhibiting oxidative stress and reducing apoptosis (Cao et al, 2022). Therefore, we treated the diabetic model with TFP5 in the present study.…”

Insulin‐like growth factor 1 knockdown attenuates high glucose‐induced podocyte injury by promoting the JAK2/STAT signalling‐mediated autophagy

“…3 Patients with DN have increased proteinuria and decreased glomerular filtration rate. 4 Hyperglycemia is considered a main risk factor for DN. 5 Nonetheless, the potential mechanisms underlying the effects of hyperglycemia are not very unclear.…”

“…Additionally, it was estimated ~38.8% and 23% of ESRD cases were caused by DN in the United States and China, respectively 3 . Patients with DN have increased proteinuria and decreased glomerular filtration rate 4 . Hyperglycemia is considered a main risk factor for DN 5 .…”