Protein kinase C and protein kinase A are involved in the protection of recombinant human glucagon‐like peptide‐1 on glomeruli and tubules in diabetic rats

Abstract

Aims/Introduction Blockade or reversal the progression of diabetic nephropathy is a clinical challenge. The aim of the present study was to examine whether recombinant human glucagon‐like peptide‐1 (rh GLP ‐1) has an effect on alleviating urinary protein and urinary albumin levels in diabetic rats. Materials and Methods Streptozotocin‐induced diabetes rats were treated with rh GLP ‐1 insulin and saline. Using immunostaining, hematoxylin–eosin, electron microscopy and periodic acid–Schiff staining to study the pathology of diabetic nephropathy, and we carried out quantitative reverse transcription polymerase chain reaction, western blot and immunohistochemistry to identify the differentially expressed proteins. The mechanism was studied through advanced glycation end‐products‐induced tubular epithelial cells. Results rh GLP ‐1 inhibits protein kinase C (PKC)‐β, but increases protein kinase A (PKA) , which reduces oxidative stress in glomeruli and in cultured glomerular microvascular endothelial cells. In tubules, rh GLP ‐1 increased the expression of two key proteins related to re‐absorption – megalin and cubilin – which was accompanied by downregulation of PKC ‐β and upregulation of PKA . On human proximal tubular epithelial cells, rh GLP ‐1 enhanced the absorption of albumin, and this was blocked by a PKC activator or PKA inhibitor. Conclusions These findings suggest that rh GLP ‐1 can reverse diabetic nephropathy by protecting both glomeruli and tubules by inhibiting PKC and activating PKA .

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

“…GLP-1RAs have been shown to prevent renal oxidative stress by inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase through the activation of PKA and the production of cyclic adenosine monophosphate (cAMP). Recombinant human GLP-1 inhibits protein kinase C (PKC)-β, but increases protein kinase A (PKA), which reduces oxidative stress in both glomeruli and tubules ( Yin et al., 2019 ). Consistent with this observation, the combination of olmesartan and exenatide has been shown to attenuate the renal NADPH oxidase 4 (Nox4) expression in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats ( Rodriguez et al., 2020 ).…”

Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets

“…PKC inhibition decreased albuminuria and improved renal function, possibly by preventing the upregulation of TGF‐β signalling . Moreover, the protective effect of recombinant human GLP‐1 in diabetic rats appears to be partly mediated by PKC inhibition and PKA activation . In a small trial in T2D patients, ruboxistaurin slightly decreased albuminuria and contributed to GFR maintenance after 1 year of treatment .…”

Renoprotective Effects of DPP-4 Inhibitors

“…GLP-1 prevents renal oxidative stress by inhibiting NADPH oxidase through the activation of PKA and the production of cAMP. Recombinant human GLP-1 reduces PKC-β but increases protein PKA, which reduces oxidative stress in both glomeruli and tubules [ 39 ]. GLP-1 induces anti-inflammatory effects by downregulating reactive oxygen species (ROS) generation in vascular cells [ 40 , 41 ] and renal cells [ 42 , 43 ].…”

“…BNP is clinically used for the diagnosis and evaluation of CVD [ 69 ]. BNP is synthesized as a 134-amino acid precursor (prepro BNP) that is processed to proBNP [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , …”