Korean J Physiol Pharmacol.  2022 Jan;26(1):1-13. 10.4196/kjpp.2022.26.1.1.

Kidney protective potential of lactoferrin: pharmacological insights and therapeutic advances

• Zahan MS
• Ahmed KA
• Moni A
• Sinopoli A
• Ha H
• Uddin MJ

• KMID: 2524506
• DOI: http://doi.org/10.4196/kjpp.2022.26.1.1

Abstract

Kidney disease is becoming a global public health issue. Acute kidney injury (AKI) and chronic kidney disease (CKD) have serious adverse health outcomes. However, there is no effective therapy to treat these diseases. Lactoferrin (LF), a multi-functional glycoprotein, is protective against various pathophysiological conditions in various disease models. LF shows protective effects against AKI and CKD. LF reduces markers related to inflammation, oxidative stress, apoptosis, and kidney fibrosis, and induces autophagy and mitochondrial biogenesis in the kidney. Although there are no clinical trials of LF to treat kidney disease, several clinical trials and studies on LF-based drug development are ongoing. In this review, we discussed the possible kidney protective mechanisms of LF, as well as the pharmacological and therapeutic advances. The evidence suggests that LF may become a potent pharmacological agent to treat kidney diseases.

Keyword

Drug development; Kidney disease; Lactoferrin; Pharmacology; Therapeutics

Figure

• 

  Fig. 1 Crystal structures of (A) bovine lactoferrin (bLF, PDB code = 1BLF), and (B) human lactoferrin (1LFG). AS1, AS2, AS3, AS4, and AS5 indicate the active sites of LF.

• 

  Fig. 2 Mechanisms of lactoferrin (LF) against AKI. Hyperoxia (FiO2 > 95 %) induces inflammation via ROS generation, MAPK and NF-κB activation. LF inhibits inflammation by reducing ROS generation and downregulating pro-inflammatory cytokines. PDC significantly increases NF-κB, IL-18, IL-4, and IGF-1 accompanied by kidney MDA and decreased GSH. Increased IL-4 leads to TNF-α expression and inflammation. IGF-1 enhances FoxO1 production, leading to tubular epithelial hyperplasia. Increased MDA leads to oxidative stress. PDC also increases Bax and caspase-3, resulting in apoptosis. LF prevents AKI by inhibiting PDC-induced inflammation, hyperplasia, apoptosis, and oxidative stress. Fe-NTA lowers the GSH content that causes oxidative stress. LF normalizes GSH and inhibits oxidative stress. Also, cisplatin causes cisplatin accumulation in the kidney that leads to tubular necrosis. LF decreases platinum content in the kidney, prevents cisplatin accumulation and inhibits tubular injury. AKI, acute kidney injury; Bax, BCL2 associated X; Fe-NTA, ferric nitrilotriacetate; FiO2, the fraction of inspired oxygen; FoxO1, forkhead box protein O1; GSH, glutathione; IGF-1, insulin-like growth factor-1; IL, interleukin; MDA, malondialdehyde; NF-κB, nuclear factor kappa B; PCNA, proliferating cell nuclear antigen; PDC, potassium dichromate; TNF-α, tumor necrosis factor alpha; MAPK, mitogen-activated protein kinase; ROS, reactive oxygen species.

• 

  Fig. 3 Mechanisms of lactoferrin (LF) against CKD. LF induces autophagy by activating AMPK and inhibiting the Akt/mTOR pathway. Hydrogen peroxide (H2O2) causes oxidative stress-induced cell death and apoptosis. LF inhibits cell death and apoptosis by augmenting autophagy and reducing caspase-3. Folic acid induces kidney fibrosis, and LF prevents that by inhibiting apoptosis and inducing autophagy. TGF-β1 induces fibrosis by increasing the expression of PAI-1, CTGF, and collagen-1, and LF inhibits fibrosis by decreasing their expression. A high fat and salt condition promotes inflammation leading to kidney damage. LF inhibits inflammation and protects against kidney damage by reducing inflammatory cytokines. AKT, protein kinase B; AMPK, AMP-activated protein kinase; Bax, BCL2 associated X; CKD, chronic kidney disease; Col1, collagen 1; CTGF, connective tissue growth factor; IL, interleukin; LC3, light chain 3; MCP-1, monocyte chemoattractant protein-1; mTOR, mechanistic target of rapamycin; PAI-1, plasminogen activator inhibitor-1; TGF-β1, transforming growth factor beta 1; α-SMA, alpha-smooth muscle actin.

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