Klotho-derived peptide 1 inhibits cellular senescence in the fibrotic kidney by restoring Klotho expression via posttranscriptional regulation

Abstract

Background: Klotho deficiency is a common feature of premature aging and chronic kidney disease (CKD). As such, restoring Klotho expression could be a logic strategy for protecting against various nephropathies. In this study, we demonstrate that KP1, a Klotho-derived peptide, inhibits cellular senescence by restoring endogenous Klotho expression. Methods: The effects of KP1 on cellular senescence and Klotho expression were assessed in mouse models of CKD. RNA-sequencing was employed to identify the microRNA involved in regulating Klotho by KP1. Gain- or loss-of-function approaches were used to assess the role of miR-223-3p and IncRNA-TUG1 in regulating Klotho and cellular senescence. Results: KP1 inhibited senescence markers p21, p16 and γ-H2AX in tubular epithelial cells of diseased kidneys, which was associated with its restoration of Klotho expression at the posttranscriptional level. Profiling of kidney microRNAs by RNA sequencing identified miR-223-3p that bound to Klotho mRNA and inhibited its protein expression. Overexpression of miR-223-3p inhibited Klotho and induced p21, p16 and γ-H2AX, which were negated by KP1. Conversely, inhibition of miR-223-3p restored Klotho expression, inhibited cellular senescence. Furthermore, miR-223-3p interacted with lncRNA-TUG1 and inhibited its expression. Knockdown of lncRNA-TUG1 increased miR-223-3p, aggravated Klotho loss and worsened cellular senescence, whereas KP1 mitigated all these changes. Conclusion: These studies demonstrate that KP1 inhibits cellular senescence and induces Klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1. By restoring endogenous Klotho, KP1 elicits a broad spectrum of protective actions and could serve as a promising therapeutic agent for fibrotic kidney disorders.

Klotho-derived peptide KP1 ameliorates SARS-CoV-2-associated acute kidney injury

“…We recently reported the discovery of KP1, a Klotho-derived peptide that exhibits kidney protective potential ( Yuan et al, 2022 ; Zhang et al, 2024 ). This prompted us to test whether KP1 can prevent kidney tubular cells from injury caused by SARS-CoV-2 N protein.…”

Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets

“…MFAP4 knockout mice exhibit reduced activation of the TGF-β/Smad pathway compared to wild-type mice after unilateral ureteral obstruction, leading to less renal fibrosis in the MFAP4-deficient state [257]. Additionally, Klothoderived peptide (KP)1 has been shown to provide protection against TGF-β/Smad-driven renal fibrosis in mice [88,259,260]. KP1 works by blocking TGF-β-induced activation of Smad2/3, and thus reduces renal fibrosis and damage [88].…”