Kidney Week

Abstract: TH-PO0573

Soluble Alpha Klotho for Reversal of Renal Interstitial Fibrosis and Renal Regeneration: A Hypothesis Based on Developmental Biology and Preclinical Evidence

Session Information

• Development, Stem Cells, and Regenerative Medicine
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Author

• Nijhawan, Pranay, Mata Gujri Hospital, Mangal Bazar , Tilak nagar, New Delhi, Delhi, India

Pranay Nijhawan, MBBS

Background

Renal interstitial fibrosis represents the final common pathway of chronic kidney disease (CKD) irrespective of its cause. α-Klotho exists in three subfamilies (α, β, γ), with α-Klotho present in membrane-bound and soluble forms. The membrane-bound form plays a key role in phosphate and vitamin D metabolism via FGF23 signaling. The soluble form (sαKL) acts as a hormone with anti-inflammatory, antioxidant, tumor-suppressive, and proteolytic activities. In-utero, sαKL levels are high and promote renal hypertrophy and hyperplasia. These levels decline after birth and further with aging and CKD¹.

Methods

Reviewed preclinical studies evaluating the therapeutic effects of exogenous Klotho supplementation and gene therapy in animal models of CKD. This includes administration of recombinant human Klotho protein (rh-Klotho), intravenous Klotho-derived peptide (KP1), gene delivery using Klotho-carrying plasmids, and mesenchymal stem cells aimed at restoring fetal levels of sαKL. Outcomes included renal function parameters, histological assessments, and molecular markers of fibrosis and regeneration.

Results

Administration of rh-Klotho (20 µg/kg/day for 8 weeks) improved glomerular filtration rate (GFR), reversed renal fibrosis, and upregulated BMP-7 expression². KP1 localized selectively to injured kidneys and reduced fibrotic lesions³. Exogenous sαKL decreased albuminuria, serum creatinine, mesangial expansion, glomerular hypertrophy, and tubular interstitial fibrosis^2,3. sαKL also increased BMP-7, which antagonized TGFβ1-induced epithelial-to-mesenchymal transition (EMT), a key process in fibrosis. Gene therapy using Klotho plasmids provided renal protection and reduced structural damage⁴. Developmental insights support that high fetal sαKL levels stimulate renal growth.

[1] Takenaka T et al. Kidney Blood Press Res. 2023;48(1):326–337.
[2] Yuan Q et al. Nat Commun. 2022;13:438.
[3] Hajare AD et al. Mol Biomed. 2025;6:19.
[4] Acta Pharmacol Sin. https://doi.org/10.1111/apha.14220

Conclusion

Supplementation of soluble α-Klotho in higher animal models at an equivalent dose for 8 weeks is necessary for the reversal of renal interstitial fibrosis. Mimicking fetal sαKL levels through such supplementation may stimulate renal regeneration in CKD and represents a promising therapeutic strategy.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20255sxcfg5a