Klotho and kidney disease

Abstract

Klotho is a single-pass transmembrane protein that exerts its biological functions through multiple modes. Membrane-bound Klotho acts as coreceptor for the major phosphatonin fibroblast growth factor-23 (FGF23), while soluble Klotho functions as an endocrine substance. In addition to in the distal nephron where it is abundantly expressed, Klotho is present in the proximal tubule lumen where it inhibits renal Pi excretion by modulating Na-coupled Pi transporters via enzymatic glycan modification of the transporter proteins - an effect completely independent of its role as the FGF23 coreceptor. Acute kidney injury (AKI) and chronic kidney disease (CKD) are states of systemic Klotho deficiency, making Klotho a very sensitive biomarker of impaired renal function. In addition to its role as a marker, Klotho also plays pathogenic roles in renal disease. Klotho deficiency exacerbates decreases in, while Klotho repletion or excess preserves, glomerular filtration rate in both AKI and CKD. Soft tissue calcification, and especially vascular calcification, is a dire complication in CKD, associated with high mortality. Klotho protects against soft tissue calcification via at least 3 mechanisms: phosphaturia, preservation of renal function and a direct effect on vascular smooth muscle cells by inhibiting phosphate uptake and dedifferentiation. In summary, Klotho is a critical molecule in a wide variety of renal diseases and bears great potential as a diagnostic and prognostic biomarker as well as for therapeutic replacement therapy.

Fig. 1

Proposed model of how Klotho regulates NaPi-2a in the apical membrane of the renal proximal tubule. Klotho functions acutely as a direct extracellular enzyme deglycosylating NaPi-2a protein and/or a putative regulatory protein (black) to reduce transport activity (no. 1 in fgure). the deglycosylated NaPi-2a is sensitized to resident protease(s) in brush border membrane (BBM) and is proteolytically degraded (no. 2). Several hours later, deglycosylated NaPi-2a protein is endocytosed from BBM into the intracellular pool (no. 3).

Fig. 2

Proposed model of Klotho effect on acute kidney injury. Ischemia-reperfusion injury (IRI) down-regulates Klotho by 3 hours after injury (no. 1). IRI causes kidney damage (no. 2). Damaged tubules further decrease Klotho expression (no. 3). Reduced Klotho renders kidney more prone to further damage (no. 4).

Fig. 3

Urinary Klotho protein in chronic kidney disease (CKD) patients normalized to creatinine in spot samples from 13 normal volunteers and 40 CKD patients. For measurement of urinary Klotho protein, 4-ml fresh urine was concentrated to 0.2 ml through Amicon ultra-4 filters with 100-kDa cutoff. Concentrated urines (with identical urine creatinine) along with recombinant murine Klotho (rMKl) protein of known concentration were subject to immunoblot. Klotho protein concentrations in urine samples were quantifed using the rMKl as a standard curve (66). *p<0.05; **p<0.01, vs. normal subjects by 1-way ANOVA followed by Student-Newman-Keuls test.

Fig. 4

Correlation of calcium content in the kidneys, hearts and aortas in sham and chronic kidney disease (CKD) mice. Calcium content was assayed using o-cresolphthalein complexone (OCPC) in the kidney, heart and aortas of sham and CKD mice at different genetic Klotho levels: Kl^+/− (light gray) and Tg-Kl (black gray) and their wild-type (WT) littermates (dark gray). For given concentration of blood creatinine (Cr) or phosphate (Pi) (vertical dotted line) Kl^+/− (light gray) mice have the highest, and Tg-Kl (black) the lowest and their WT littermates (dark gray) intermediate levels of Ca content in soft tissues.

Fig. 5

Proposed model of potential effects of Klotho on the kidney progression and vascular calcification in chronic kidney disease (CKD). Klotho protects the vasculature against calcification in CKD probably by 3 actions: slowing progression of CKD (no. 1); maintenance of normophosphatemia through induction of phosphaturia (no. 2); direct inhibition of phosphate (Pi) infulx into vascular smooth muscle cells (VSMCs), which in turn suppresses the dedifferentiation of VSMCs (no. 3). Ca × P = calcium × phosphorus product; PtH = parathyroid hormone.