Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection

Abstract

Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD.

Cross-Domain Text Mining of Pathophysiological Processes Associated with Diabetic Kidney Disease

“…The cellular signaling responses include growth factor signaling, the response to nitric oxide, the response to oxidative stress, the cytokine response, macrophage signaling, the TLR pathway, the T-cell-mediated response, NFκB factor activity, ERK/MAPK signaling, the JAK/STAT pathway, the WNT/β-catenin pathway, and NADPH oxidase activity. Several of these pathways are known to be implicated in GEC injury, inflammation, and fibrosis associated with DKD [6,8,11,17]. Similarly, the analyses suggested that the apoptotic processes, the response to cytokines, the T-cell-mediated response, the immune response, calcium channel activity, and growth factor signaling were the most frequent and active biological processes in DKD (Figures 6 and 7).…”

“…The pathophysiology of DKD is multi-factorial and characterized by metabolic impairment, an uncontrolled inflammatory response, increased apoptosis, and tissue fibrosis [4,6]. In diabetes, aberrant glucose metabolism leads to dysregulation of the immune response and signaling [6][7][8]. Metabolic abnormalities activate the mononuclear phagocyte system, which releases pro-inflammatory cytokines and paracrine signals, leading to immune cell infiltration [6][7][8][9].…”

“…In diabetes, aberrant glucose metabolism leads to dysregulation of the immune response and signaling [6][7][8]. Metabolic abnormalities activate the mononuclear phagocyte system, which releases pro-inflammatory cytokines and paracrine signals, leading to immune cell infiltration [6][7][8][9]. In the early stages of diabetes, glomerular and tubular cells have increased expression of tumor necrosis factor (TNF) α, interleukin (IL)-6, IL-1, and adhesion molecules [10,11].…”

“…The dysregulated signaling response leads to progressive kidney damage through loss of glomerular endothelial fenestrations, thickening of the basement membrane, the detachment of podocyte foot processes, mesangial matrix expansion, and glomerular fibrosis [7,[14][15][16][17]. For excellent illustrations of the pathological processes, readers are referred to [7,8,16,17].…”