Klotho: Gene Therapy for Chronic Kidney Disease

Chronic kidney disease (CKD) affects 10 percent of the global population. As the world’s aging population grows, so will this number.

For nearly 30 years, mounting evidence from multiple studies has correlated Klotho deficiency with the onset and progression of CKD (Zou, 2018).

Klotho is a gene often highlighted for its role in aging and cognitive health. Deficiency of Klotho has a well-established correlation with shorter lifespans, age-related pathologies, and neurodegeneration. (Kanbay, 2023)

Klotho overexpression yields a fascinating contrast: an abundance of this protein led to a 30% increase of lifespan in mice, while deficiency led to conditions comparable to human aging: muscle wasting, thin skin, infertility, osteoporosis, arteriosclerosis, and others (Vo, 2018).

Klotho’s cognitive benefits are vast; overexpression in the brain is correlated with enhanced cognition and memory in nonhuman primates, along with increased synaptic plasticity and cognition in mice (Castner, 2023).

Klotho is produced in the kidneys and its presence is correlated with healthy renal function. CKD’s early stages are accompanied by its decline. This has led researchers to see Klotho as a viable biomarker for CKD (Wang, 2018).

Even those who are on the fence about its usefulness as a biomarker readily concede to its beneficial pleiotropic role in the kidney (Yu, 2022).

Klotho also reduces inflammation. The inflammatory effects of CKD are palpable, and evidence suggests Klotho mitigates inflammatory responses, this occurs likely because it lowers the activity of NF-κB (Maekawa, 2009).

NF-kB switches on pro-inflammatory genes (Liu, 2017). Studies also point to a protein called TNF, which increases VCAM-1 and ICAM-1, molecules that play a role in various inflammatory conditions. Klotho counteracts this by mitigating TNF's action upon them (Maekawa, 2009).

It has also been discovered that overexpression can inhibit another pathway (PDLIM2/NF-κB) to decrease the production of the inflammatory compounds TNF-α, IL-6, and IL-12, helping prevent kidney damage that can be caused by cyclosporine A, an immunosuppressant drug used after organ transplants (Jin, 2017).

Klotho’s kidney-specific anti-inflammatory action is further bolstered by reducing Nox2, a protein linked to oxidative stress (Singel, 2016). Klotho downregulates Nox2 expression and was found to decrease oxidative damage, and cellular death (Wang, 2012).

Vascular calcification (VC), the “hardening of the arteries,” a process by which calcium forms hard crystals in the walls of blood vessels, manifests early in CKD. It becomes more widespread as renal function deteriorates, increasing the risk of cardiovascular death (Zou, 2018).

Klotho is seen as a potential candidate in linking CKD and cardiovascular mortality, as vascular abnormalities and dysfunction are increased with klotho deficiency (Zou, 2018).

Klotho helps prevent VC by blocking the movement of phosphate in vascular cells and arresting the processes that cause these cells to transform into bone-forming cells. In healthy people it mitigates calcification and mineral buildup in blood vessels, maintaining function and integrity of endothelial cells, responsible for blood flow, inflammation, and vascular tone (Vervloet, 2014).

Often the final manifestation of CKD is renal fibrosis. This scarring comes from the kidney’s inability to heal.

The confluence of chronic damage touches the kidney tubules, responsible for returning nutrients and fluids to the body, and the glomeruli, which filter the blood.

Kidney injury prompts the release of transforming growth factor β (TGF-β), which leads to increased damage and fibrosis.

Diminished Klotho levels aggravate TGF-β activity, worsening fibrosis. A wealth of studies have shown that TGF-β is a key of the profibrotic regulator in progressive CKD. Klotho can block TGF-β signaling, and reduce fibrosis (Zou, 2018).

But Klotho does not only work against TGF-β signaling. Another major malefactor here is Angiotensin II (Ang II). This molecule, which causes an increase in blood pressure, excites aldosterone release, and sodium retention, also exerts pro-inflammatory and pro-fibrotic effects in the kidney (Benigni, 2010).

Klotho’s downregulation likely plays a role in the progression of renal damage induced by Ang-II, while its induction minimizes damage, making it a potential candidate for treating Ang II-induced organ damage (Mitani, 2002).

As a multi-pronged therapeutic of potentially tremendous value in the treatment and prevention of CKD, it is clear that Klotho gene therapy should be a therapeutic intervention explored for human patients.

Of course, maintaining optimal health will require many genes, which can only be delivered with a better vector.

CKD may affect over a billion people in the near future, so it is paramount that promising treatments arrive sooner rather than later. For nearly three decades mounting evidence has pointed to Klotho as a remarkably versatile and powerful protein.

Why is it not available yet?

Best Choice Medicine provides an avenue for us to take necessary steps to ensure Klotho and other life-saving therapeutics are available to the countless patients who need them.

References and Works Cited

Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010 Jul;2(7):247-57. doi: 10.1002/emmm.201000080. PMID: 20597104; PMCID: PMC3377325.

Castner, S.A., Gupta, S., Wang, D. et al. Longevity factor klotho enhances cognition in aged nonhuman primates. Nat Aging 3, 931–937 (2023). https://doi.org/10.1038/s43587-023-00441-x

Jin M, Lv P, Chen G, Wang P, Zuo Z, Ren L, Bi J, Yang CW, Mei X, Han D. Klotho ameliorates cyclosporine A-induced nephropathy via PDLIM2/NF-kB p65 signaling pathway. Biochem Biophys Res Commun. 2017 Apr 29;486(2):451-457. doi: 10.1016/j.bbrc.2017.03.061. Epub 2017 Mar 16. PMID: 28315683.

Kanbay M, Copur S, Ozbek L, Mutlu A, Cejka D, Ciceri P, Cozzolino M, Haarhaus ML. Klotho: a potential therapeutic target in aging and neurodegeneration beyond chronic kidney disease-a comprehensive review from the ERA CKD-MBD working group. Clin Kidney J. 2023 Nov 3;17(1)
. doi: 10.1093/ckj/sfad276. PMID: 38213484; PMCID: PMC10783249.

Liu, T., Zhang, L., Joo, D. et al. NF-κB signaling in inflammation. Sig Transduct Target Ther 2, 17023 (2017). https://doi.org/10.1038/sigtrans.2017.23

Maekawa Y, Ishikawa K, Yasuda O, Oguro R, Hanasaki H, Kida I, Takemura Y, Ohishi M, Katsuya T, Rakugi H. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine. 2009 Jun;35(3):341-6. doi: 10.1007/s12020-009-9181-3. Epub 2009 Apr 15. PMID: 19367378.

Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S, Suzuki T, Amaki T, Mori I, Nakamura Y, Sato M, Nangaku M, Hirata Y, Nagai R. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension. 2002 Apr;39(4):838-43. doi: 10.1161/01.hyp.0000013734.33441.ea. PMID: 11967236.

Singel KL, Segal BH. NOX2-dependent regulation of inflammation. Clin Sci (Lond). 2016 Apr 1;130(7):479-90. doi: 10.1042/CS20150660. PMID: 26888560; PMCID: PMC5513728.

Vervloet MG, Adema AY, Larsson TE, Massy ZA. The role of klotho on vascular calcification and endothelial function in chronic kidney disease. Semin Nephrol. 2014 Nov;34(6):578-85. doi: 10.1016/j.semnephrol.2014.09.003. PMID: 25498377.

Vo HT, Laszczyk AM, King GD. Klotho, the Key to Healthy Brain Aging? Brain Plast. 2018 Aug 10;3(2):183-194. doi: 10.3233/BPL-170057. PMID: 30151342; PMCID: PMC6091049.

Wang Q, Su W, Shen Z, Wang R. Correlation between Soluble α-Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis. Biomed Res Int. 2018 Aug 12;2018:9481475. doi: 10.1155/2018/9481475. PMID: 30159331; PMCID: PMC6109492.

Wang Y, Kuro-o M, Sun Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. Aging Cell. 2012 Jun;11(3):410-7. doi: 10.1111/j.1474-9726.2012.00796.x. Epub 2012 Feb 22. PMID: 22260450; PMCID: PMC3342395.

Yu LX, Li SS, Sha MY, Kong JW, Ye JM, Liu QF. The controversy of klotho as a potential biomarker in chronic kidney disease. Front Pharmacol. 2022 Sep 21;13:931746. doi: 10.3389/fphar.2022.931746. PMID: 36210812; PMCID: PMC9532967.

Zou D, Wu W, He Y, Ma S, Gao J. The role of klotho in chronic kidney disease. BMC Nephrol. 2018 Oct 22;19(1):285. doi: 10.1186/s12882-018-1094-z. PMID: 30348110; PMCID: PMC6198535