Recent Advances in the Emerging Therapeutic Strategies for Diabetic Kidney Diseases

Abstract

Diabetic kidney disease (DKD) is one of the most common causes of end-stage renal disease worldwide. The treatment of DKD is strongly associated with clinical outcomes in patients with diabetes mellitus. Traditional therapeutic strategies focus on the control of major risk factors, such as blood glucose, blood lipids, and blood pressure. Renin-angiotensin-aldosterone system inhibitors have been the main therapeutic measures in the past, but the emergence of sodium-glucose cotransporter 2 inhibitors, incretin mimetics, and endothelin-1 receptor antagonists has provided more options for the management of DKD. Simultaneously, with advances in research on the pathogenesis of DKD, some new therapies targeting renal inflammation, fibrosis, and oxidative stress have gradually entered clinical application. In addition, some recently discovered therapeutic targets and signaling pathways, mainly in preclinical and early clinical trial stages, are expected to provide benefits for patients with DKD in the future. This review summarizes the traditional treatments and emerging management options for DKD, demonstrating recent advances in the therapeutic strategies for DKD.

Keywords: SGLT2 inhibitors; diabetic kidney disease; fibrosis; inflammation; therapeutics.

Figure 1

The renoprotective mechanisms of SGLT2 inhibitors. The molecular mechanisms of SGLT2 under hyperglycemia conditions with and without SGLT2 inhibitor. (a) SGLT2 is upregulated under hyperglycemic conditions. The reabsorption of sodium and glucose increased, which resulted in the activation of Na⁺-K⁺ ATPase, thus leading to increased ATP and oxygen consumption and mitochondrial damage. The increased resorption of sodium resulted in the low sodium concentration in the macula densa and activated tubuloglomerular feedback, causing the vasodilation of afferent arterioles and increased intraglomerular pressure. (b) SGLT2 inhibitors reversed the above changes through inhibiting the resorption of sodium and glucose and increasing the sodium concentration in the macula densa, leading to afferent arteriole constriction and reduced intraglomerular pressure. SGLT2, sodium-dependent glucose transporters 2; ATP, adenosine triphosphate; ADP adenosine diphosphate; AMP, adenosine monophosphate; Na⁺-K⁺ ATPase: sodium-potassium ATPase. Upper arrow in red indicates increase; down arrow in blue indicates decrease.

Figure 2

The renoprotective mechanisms of DPP-4 inhibitors. DPP-4 inhibitors can exert renoprotective effects dependent on or independent of the incretin. GLP-1, an identified incretin, works by the activation of GLP-1R. GLP-1 is rapidly degraded by DDP-4 after exerting its effects. After inhibiting the degradation of GLP-1, DPP-4 inhibitors resulted in decreased blood glucose, improved hypertension by inhibiting Ang II, protected endothelial function by inhibiting ET-1, and inhibited NHE3 to exert natriuretic effect. On the other hand, DPP-4 inhibitors inhibited oxidative stress and improved renal fibrosis by regulating SDF-1, collagen I, Apo-C1 and other substrates independent of GLP-1 and its receptors. DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide 1; GLP-1R, glucagon-like peptide 1 receptor; SDF-1, stromal cell-derived factor 1; Apo-C1, apolipoprotein C1; Ang II, angiotensin II; ET-1, endothelin-1; NHE3, sodium-hydrogen exchanger 3. Upper arrow in red indicates increase; down arrow in blue indicates decrease; down arrow in black indicates the direction of blood flow.