Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights

Abstract

Background: Diabetic kidney disease (DKD) is a chronic kidney condition that arises from prolonged hyperglycaemia that can progress to kidney failure, severe morbidity, and mortality if left untreated. It is the major cause of chronic kidney disease among people who have diabetes, accounting for a significant percentage of patients with end-stage kidney disease who require kidney replacement therapy.

Main body: In DKD, numerous dysbalanced metabolic, haemodynamic, inflammatory signalling pathways, and molecular mediators interconnect, creating a feedback loop that promotes general kidney damage. Hyperglycaemia is the primary trigger for DKD and leads gradually to oxidative stress, inflammation, extracellular matrix deposition and fibrosis, glomerular hypertension, and intrarenal hypoxia. Key interconnected metabolic pathways are the hyperglycaemia-mediated polyol, hexosamine, protein kinase C, and advanced glycation end-products pathway hyperactivity. Concurrently, hyperglycaemia-induced renin-angiotensin-aldosterone system stimulation, alters the kidney intraglomerular haemodynamic leading to inflammation through Toll-like receptors, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappa B, transforming growth factor-beta-mediated excessive extracellular matrix accumulation and fibrosis. The resulting death signals trigger apoptosis and autophagy through Hippo, Notch, and Wnt/β-catenin pathway activation and microRNA dysregulation. These signals synergistically remodel the kidneys culminating in intrarenal hypoxia, podocyte dysfunction, hyperfiltration, epithelial-mesenchymal transition, and loss of kidney function. The resulting renal failure further upregulates these death pathways and mediators, giving rise to a vicious cycle that further worsens DKD.

Conclusion: This review provides an overview of the primary molecular mediators and signalling pathways leading to DKD; their interconnectivity at the onset and during DKD progression, the central role of transforming growth factor-beta via different pathways, the Hippo pathway kidney-specific response to hyperglycaemia, and how all mediators and transduction signals result in a vicious circle that exacerbates renal failure. The review gives therapeutic sights to these pathways as druggable targets for DKD management. Understanding these molecular events underlying the pathogenesis of DKD can bridge basic research and clinical application, facilitating the development of innovative management strategies.

Keywords: Chronic kidney disease; Diabetic nephropathy; End-stage kidney disease; Hippo signalling; Janus kinase/signal transducer and activator of transcription; Nuclear factor-kappa B; Renin–angiotensin–aldosterone system; Signal pathways; Toll-like receptors; Transforming growth factor-beta.

Fig. 1

Contribution of chronic hyperglycaemia to increased polyol pathway flux and diabetic kidney disease progression. Increased polyol pathway nux increases oxidative stress, activates the mitogcn-activatcd protein kinase (MAPK), rapidly accelerates fibrosareoma (Raf), mitogcn­activated protein kinase (MEK), extracellular signal-regulated kinases I and 2 (ERKl/2), and transcription factors activator protein-I (AP-I). Increased oxidative stress increases intracellular fructose, causes diacylglycerol (DAG) accumulation, protein kinase C (PKC)/nicotinamide adenine dinuclcotidc phosphate (NADPH) oxidasc activation, and increased reactive oxygen species (ROS). ROS further activates adcnyl cyclase through a series of reactions that culminates in increased transforming growth factor-beta (TGF-β). AP-I and PKC activation also results in high expression of TGF-β. All of which results in extracellular matrix (ECM) accumulation. glomcrular basement membrane (GHM) thickening. and ultimately DKD development

Fig. 2

Mechanisms underpinning inflammatory processes related to fibrosis in DKD. Hyperglycaemia induces an inflammatory response in the kidneys through the recruitment of immune cells and release of inflammatory cytokines and chemokines, These mediators drive the process of fibrosis with the release of TGF-β, resulting in epithelial/endothelial cell transition and activation of fibroblasts/pericytes. This process leads to the formation of mesenchymal cells, myofibroblasts, excess extracellular matrix accumulation, and, ultimately, fibrosis of the kidney

Fig. 3

Activation of transforming growth factor 1 (TGF-β1) signalling in the development of DKD. Hyperglycaemia results in increased advanced glycation end products (AGEs) which bind to its receptor (RAGE), resulting in ROS generation in kidney cells. It also upregulates the transcription of the TGF-β1 gene, giving rise to TGF-β1 production. TGF-β1 interacts with key inflammatory and fibrotic pathways, including extracellular signal­ regulated kinase (ERK), p38, and the Smad cascade, to drive fibrotic gene transcription in the nucleus, promoting mesangial expansion and fibrosis. Hyperglycaemia further activates angiotensin II (Angil), which engages the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, further promoting epithelial-mesenchymal transition (EMT) formation and ultimately fibrosis. The mechanistic target of rapamycin (mTOR) and nuclear factor-kappa B (NF-κB) promotes ECM deposition as well through the non-Smad pathway

Fig. 4

Hyperactivation of Ang II and renal extracellular matrix modelling. Chronic hyperglycaemia activates angiotensin II (Angll), which results in proteinuria, inflammation, macrophage infiltration, elevated glomerular capillary pressure and permeability. All these processes release inflammatory and profibrotic cytokines leading to extracellular matrix remodelling

Fig. 5

Hippo signalling contributes to renal fibrosis and damage in diabetic conditions. The core Hippo pathway comprises a kinase cascade involving MSTl/2 and LATSl/2. In diabetic conditions, when the pathway is switched on, YAP/TAZ phosphorylate, leading to YAP/TAZ inhibition, thus preventing their nuclear translocation and downstream gene activation. When the pathway is off, YAP/TAZ translocates to the nucleus to activate downstream genes involved in fibrosis. Dysregulated Hippo signalling in the diabetic kidney results in decreased MSTl/2 activity, which favours YAP/TAZ translocation to the nucleus, where they promote fibrosis by activating profibrotic genes such as CTGF and TGF-β1. The TGF-β signalling pathway via Smad 1 and 4 (Smad-dependent and non-Smad pathways) activates the translocation of the Smad 1/4/YAP/TAZ complex into the kidney, which upregulates fibrotic markers, leading to epithelial-mesenchymal transition (EMT) and extracellular matrix (ECMJ accumulation, thereby amplifying renal fibrosis