Klotho's impact on diabetic nephropathy and its emerging connection to diabetic retinopathy

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide and is a significant burden on healthcare systems. α-klotho (klotho) is a protein known for its anti-aging properties and has been shown to delay the onset of age-related diseases. Soluble klotho is produced by cleavage of the full-length transmembrane protein by a disintegrin and metalloproteases, and it exerts various physiological effects by circulating throughout the body. In type 2 diabetes and its complications DN, a significant decrease in klotho expression has been observed. This reduction in klotho levels may indicate the progression of DN and suggest that klotho may be involved in multiple pathological mechanisms that contribute to the onset and development of DN. This article examines the potential of soluble klotho as a therapeutic agent for DN, with a focus on its ability to impact multiple pathways. These pathways include anti-inflammatory and oxidative stress, anti-fibrotic, endothelial protection, prevention of vascular calcification, regulation of metabolism, maintenance of calcium and phosphate homeostasis, and regulation of cell fate through modulation of autophagy, apoptosis, and pyroptosis pathways. Diabetic retinopathy shares similar pathological mechanisms with DN, and targeting klotho may offer new insights into the prevention and treatment of both conditions. Finally, this review assesses the potential of various drugs used in clinical practice to modulate klotho levels through different mechanisms and their potential to improve DN by impacting klotho levels.

Keywords: chronic kidney disease; diabetic nephropathy; diabetic retinopathy; drug; klotho; mechanism; type 2 diabetes mellitus.

Figure 1

Klotho structure and its mechanism of action. Klotho consists of two extracellular structural domains (KL1 and KL2), a transmembrane segment (TM), and a short non-signaling cytoplasmic tail (CYT). Enzymes such as ADAM10 or ADAM17 can cleave Klotho to produce a soluble form called s-Klotho. FGF23 binds to the Klotho/FGFR1c receptor in the renal tubule to form the Klotho/FGFR/FGF23 signaling complex, which exerts multiple actions. Klotho binds to the TGF-β receptor, specifically the TβRII component, and inhibits TGF-β and its downstream pathways and molecular activation. Klotho inhibits the activation of the inflammatory NF-κB pathway and increases signaling in the Nrf2 pathway. Klotho block IGF-1 receptor signaling as well as the expression of target genes downstream of Wnt/β-catenin. Klotho inhibits inflammation and fibrosis in diabetic nephropathy through multiple pathways. KL, Klotho; FGF23, fibroblast growth factor 23; FGFR, FGF receptor; AMAD, a disintegrin and metalloproteases; TGF-β, transforming growth factor β; TβRII, TGF-β receptor type II; Egr-1, early growth response factor 1; RAS, agents renin-angiotensin system; ROS, reactive oxygen species; TLR4, toll-like receptor 4; Nrf2, nuclear factor-erythroid 2-related factor 2; NF-κB, nuclear factor κB; IGF-1, insulin-like growth factor 1; IGF-1R, IGF-1 receptor.

Figure 2

The role of Klotho in vascular protection. (A) Klotho can activate PI3K/AKT/Nrf2/HO-1 to enhance endothelial antioxidant defense; It can also activate PI3K/Akt/eNOS pathway, and alleviate the inhibition of eNOS phosphorylation by inflammatory factors such as TNF-α, thereby promoting NO production and preventing endothelial cell dysfunction. Klotho is involved in the transmission of VEGF signaling and regulates Ca2+ influx, which helps to maintain endothelial integrity. (B) Klotho inhibits phosphate uptake by vascular smooth muscle cells (VSMCs), leading to improved vascular calcification. It also inhibits the PiT2/RUNX2 signaling pathway, which improves extracellular matrix calcification. Additionally, Klotho inhibits the Wnt7b/β-catenin signaling pathway, which prevents VSMC calcification. NO, nitric oxide; eNOS, endothelial nitric oxide synthase; PI3K, Phosphoinositide 3-kinase; AKT, protein kinase B; Nrf2, Nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; TRPC-1, transient-receptor potential canonical Ca(2+) channel 1; VEGF, vascular endothelial growth factor; PiT, Pi transporter; RUNX2, runt-associated transcription factor 2.

Figure 3

Klotho regulates cell death. Klotho regulates autophagic flux through PI3K/AKT/mTOR, MAPK, and AMPK pathways. Klotho can increase the binding of Beclin-1 to Bcl-2, reduce Beclin-1’s interaction with other autophagy-related proteins, and thereby regulate autophagy. Additionally, Klotho indirectly upregulates autophagy by inhibiting the activity of NLRP3 inflammatory vesicles, which helps prevent renal tubular cell death. Klotho also indirectly regulates autophagy by controlling the excretion of Pi. PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; AMPK, adenosine monophosphate-activated protein kinase; NLRP3, nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3; PiT, phosphate transporter.

Figure 4

The game between pathogenic factors and Klotho. Diabetic retinopathy (DR) and diabetic nephropathy (DN) are two major microvascular complications that commonly occur in late-stage diabetes. These complications share common pathogenic mechanisms. Given the multiple beneficial effects of Klotho on DN, it is reasonable to speculate that Klotho may also have a positive effect on DR.