Signaling pathways in the pathogenesis of diabetic kidney disease (review)

Abstract

Diabetic kidney disease (DKD) is widespread and poses a significant medical and social challenge. Routine DKD markers, such as albuminuria and glomerular filtration rate, do not always reflect the initial stages and progression of kidney damage. Current DKD treatments, including glycemic control and renin-angiotensin-aldosterone system (RAAS) inhibition, retain high residual risks of progression to end-stage renal failure. Dissatisfaction with diagnostic and treatment results prompts attention to poorly controlled processes, including glucose toxicity, oxidative stress, immune-mediated inflammation, hypoxia, cell death, glomerulosclerosis, and tubulointerstitial fibrosis. This article presents an overview of the key signaling pathways and molecular mediators that underlie typical pathophysiological processes. Hyperglycemia is the primary trigger for DKD, and glucose toxicity is mediated through multiple signaling pathways. Local RAAS not only affects intraglomerular hemodynamics but also leads to inflammation via toll-like receptors, kinase/signal transducer and activator of transcription, and nuclear factor kappa B, leading to excessive accumulation of extracellular matrix and fibrosis. Interconnections between cascades at the onset and progression of DKD, their regulation by positive feedback, and the central role of transforming growth factor-beta in activating various signaling pathways have been noted. The resulting death signals, through activation of the Hippo, Notch, and Wnt/β-catenin pathways, trigger autophagy, cell senescence, apoptosis, and necrosis. Stress or cell death generates mediators and signaling pathways that create vicious cycles that contribute to the progression of chronic kidney disease. Understanding signaling pathways will catalyze a paradigm shift in DKD management – from monitoring progression to targeting disease mechanisms in individual patients and from standard treatment to personalized therapy.