Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio-renal complications and guide treatment interventions in people with diabetes.

We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon-like peptide-1 (GLP-1) receptor agonists.

Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney-derived anti-ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT-2 inhibitors and GLP-1 receptor agonists all influence pathways involved in vascular ageing.

A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio-renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes.

Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate and vitamin D metabolism in the kidney, and its higher levels in plasma are associated with poorer outcomes in kidney and cardiovascular diseases. It is produced by bone cells upon enhanced oxidative stress and inhibits renal phosphate reabsorption and calcitriol (active form of vitamin D) production. Bilirubin, the final product of the heme catabolic pathway in the vascular bed, has versatile biological functions, including antioxidant and anti-inflammatory effects. This study explored whether bilirubin alters FGF23 production.

Experiments were performed using UMR106 osteoblast-like cells. Fgf23 transcript levels were determined by quantitative real-time polymerase chain reaction, C-terminal and intact FGF23 protein levels were determined by enzyme-linked immunosorbent assay, and cellular oxidative stress was assessed by CellROX assay.

Unconjugated bilirubin down-regulated Fgf23 gene transcription and FGF23 protein abundance; these effects were paralleled by lower cellular oxidative stress levels. Also, conjugated bilirubin reduced Fgf23 mRNA abundance.

Bilirubin down-regulates FGF23 production in UMR106 cells, an effect likely to be dependent on the reduction of cellular oxidative stress.

The aim of our study was to compare klotho in the serum and aqueous humor of patients with primary open-angle glaucoma (POAG), pseudoexfoliation glaucoma (PEXG) and pseudoexfoliation syndrome (PEX).

18 POAG, 20 PEXG, 19 PEX and 20 control patients were included in our study. Aqueous humor and serum samples were collected at the time of cataract surgery. Samples were collected using enzyme-linked immunosorbent assay to evaluate the levels of Klotho protein.

Klotho levels in the serum and aqueous humor of PEXG patients (34.45 ± 3.59, 0.20 ± 0.15 ng/ml), PEX (35.85 ± 4.26, 0.23 ± 0.20 ng/ml) patients and POAG patients (35.99 ± 3.73, 0.25 ± 0.20 ng/ml) were significantly lower than control group (40.14 ± 3.85, 0.53 ± 0.39 ng/ml) (PEXG, P < 0.001, P < 0.001; PEX, P = 0.002, P = 0.003; POAG, P = 0.006, P = 0.003, respectively). Both serum and aqueous levels of klotho in the PEXG and PEX patients were lower than POAG patients, but the difference did not reach statistical significance (PEXG & POAG P = 0.149, P = 0.696), (PEX & POAG P = 0.845, P = 0.775).

Klotho levels in the serum and aqueous humor decreased in PEX, PEXG and POAG groups compared to control group, but the reduction was most significant in PEXG group.

Klotho concentration may be considered as a prognostic factor in the development of chronic complications of diabetes. Moreover, decrease in sKlotho concentration may contribute to beta cell apoptosis and type 1 diabetes development. The aim of this study was to evaluate if sKlotho protein concentration in children with type 1 diabetes (T1D) and its correlation with classical risk factors of chronic complications of diabetes: dysglycemia and endothelial dysfunction.

In a cross-section single center study the levels of soluble Klotho protein in 80 T1D (37 boys) and 34 healthy children (controls, 15 boys). Micro- and macroangiopathy were excluded and renal function was normal in all participants. Serum sKlotho, sICAM-1, sVCAM-1 and E-selectin levels were measured.

The concentration of sKlotho was lower in T1D than in the controls (2041.9 ± 1017.6 pg/mL vs. 2790.3 ± 1423.9 pg/mL, p=0.0113). sICAM-1, sVCAM-1 and E-selectin concentrations were comparable in patients and controls. In T1D, sKlotho was not correlated with the duration of diabetes. Klotho and E-selectin were correlated with HbA1c (r=-0.31, P=0.0066 and r=0.25, P=0.0351, respectively), but not with AVBG and blood glucose SD. Correlations of sKlotho with total cholesterol (r=0.31, P=0.0129), HDL-cholesterol (r=0.43, P=0.0011) and LDL-cholesterol (r=0.28, P=0.0412), but not with triglycerides, were found. Likewise, Klotho was not correlated with sICAM-1, sVCAM-1, and E-selectin concentrations.

This study reports the significantly lower level of s-Klotho in children with type 1 diabetes, correlated with HbA1c and HDL cholesterol, but not with the adhesion molecules concentrations nor the duration of the disease. Negative correlation between the levels of HbA1c and soluble Klotho may suggest its possible involvement in the development of chronic diabetes complications.

Although the Klotho gene is recognized as an aging-suppressor gene, the clinical significance of its soluble product, soluble Klotho, in coronary artery disease (CAD) has not been completely determined. The relationship between soluble Klotho and coronary artery calcification (CAC) was investigated in patients with stable CAD.

CAC in culprit lesions was analyzed in 75 non-dialysis patients with stable CAD who were scheduled for percutaneous coronary intervention (PCI) following intravascular ultrasound (IVUS). The main outcome measure was the calcium index (CalcIndex), a volumetric IVUS-derived measure of total calcification per culprit lesion. A low CalcIndex was defined as a first-quartile calcium index (<0.042). Patients were divided into two groups according to the median serum Klotho value: low Klotho (n = 37, ≤460 pg/mL) and high Klotho (n = 38, >460 pg/mL).

The CalcIndex was significantly lower in patients with high than with low Klotho. Patients with high Klotho had a significantly higher prevalence of a low CalcIndex than those with low Klotho. The number of angiographic moderate-severe CACs in whole coronary arteries was significantly decreased in patients with high Klotho compared to low Klotho. Serum Klotho levels correlated significantly and inversely with the CalcIndex. This relationship was pronounced in patients with estimated glomerular filtration rate <60 mL/min/1.73 m². Logistic regression analysis showed that high Klotho was associated with a low CalcIndex independent of classical coronary risk factors and markers of mineral metabolism.

High serum soluble Klotho levels are associated with a low degree of CAC in non-dialysis, stable CAD patients treated by PCI.

Cardiovascular disease is a leading cause of death worldwide and accounts for >17.3 million deaths per year, with an estimated increase in incidence to 23.6 million by 2030. ¹ Cardiovascular death represents 31% of all global deaths ² -with stroke, heart attack, and ruptured aneurysms predominantly contributing to these high mortality rates. A key risk factor for cardiovascular disease is hypertension. Although treatment or reduction in hypertension can prevent the onset of cardiovascular events, existing therapies are only partially effective. A key pathological hallmark of hypertension is increased peripheral vascular resistance because of structural and functional changes in large (conductive) and small (resistance) arteries. In this review, we discuss the clinical implications of vascular remodeling, compare the differences between vascular smooth muscle cell remodeling in conductive and resistance arteries, discuss the genetic factors associated with vascular smooth muscle cell function in hypertensive patients, and provide a prospective assessment of current and future research and pharmacological targets for the treatment of hypertension.

Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition.

A total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; Pinteraction  < 0.01).

Low Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril.

Cellular secretory products have infinite potential, which is only recently explored for research and therapeutic applications. The present study elaborated on the formation of a unique matrix-entrapped cellular secretome (MCS), a hydrogel-like secretome produced by bone marrow-derived mononuclear cells when cultured on a three-dimensional electrospun nanofiber matrix under specific conditions. These culture conditions support the growth of a mixed population predominantly comprising of endothelial precursor cells (EPCs), along with mesenchymal stromal cells and pericytes. Interestingly, such secretome is not formed in a pure culture of EPCs on the similarly formulated matrix, suggesting that a heterotypic cell-cell interaction is essential for the formation of MCS. In addition, the specific composition of the matrix was found to be a critical necessity for the formation of MCS. Furthermore, the application of the MCS as a substrate promotes the growth of EPCs in culture. It also rescues the diabetes-induced EPC dysfunction as assessed based on the parameters, such as viability, proliferation, colony formation, cellular adhesion, chemotactic migration, and tubule formation. MCS augments the levels of eNOS-specific mRNA (Nos3) and also promotes the restoration of the SDF1/CXCR4 axis in diabetic EPCs. Notably, a topical application of MCS on diabetic wounds leads to an accelerated wound closure. Thus, the current data showed that MCS forms an excellent cell-free biomaterial in the treatment of diabetic wounds and non-healing ulcers.

Soluble Klotho (sKlotho) is a circulating hormone with cardiovascular-renal protective effects. Whether sKlotho predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) with relatively preserved renal function is unknown.

Single-center observational follow-up study of 101 patients with T2DM and eGFR >45 mL/min [91% on renin angiotensin system (RAS) blockade] followed for a median of 9 years (range, 2 to 13 years).

Primary outcome was a >50% decline in eGFR. sKlotho, serum phosphorus, serum calcium, and fibroblast growth factor-23 levels were measured from stored samples collected at baseline. Patients were followed up with standardized clinical and biochemical measurements.

Patients with residual microalbuminuria (MA) despite RAS blockade (n = 53) had significantly lower levels of sKlotho [median, 184.7 pg/mL; interquartile range (IQR), 130.5 to 271.8 pg/mL) compared with patients without MA (n = 39; median, 235.2 pg/mL; IQR, 172.0 to 289.4 pg/mL; P = 0.03). Of the cohort, 21% reached the primary outcome. In a competing risk analysis, a 10% higher sKlotho level reduced the incidence of the primary outcome by 12% (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.52; P < 0.001] independent of traditional risk factors. Patients with sKlotho below the median of 204.4 pg/mL had nearly a fourfold higher cumulative incidence of the primary outcome compared with those above the median (24% vs 6.2%; P = 0.01).

In patients with T2DM with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk markers. sKlotho is a biomarker of renal dysfunction and a potential treatment target for renoprotection in T2DM.

KLOTHO is an anti-ageing circulating hormone involved in insulin signaling, inflammation and vascular homeostasis through its protective effects on the endothelium and antioxidant actions. The common functional "KL-VS" variant of the KLOTHO gene is reproducibly associated with longevity in humans. Large number of studies have evaluated close relationship between KLOTHO protein and diabetes but the association between KL-VS variant and retinopathy in type 1 diabetes mellitus (T1D) is unknown. Therefore, in the present study we examined the association between the KL-VS polymorphism and the risk of diabetic retinopathy (DR) in patients with T1D.

We examined 400 patients with T1D and 350 healthy age-matched controls. The analysis concerned KL-VS polymorphism along with the levels of serum inflammatory (CRP, TNF-α) and anti-inflammatory (IL-10) markers, pro-angiogenic (angiogenin) and anti-angiogenic interferon gamma-induced protein 10 (IP-10) factors as well as adhesion molecules (ICAM-1, ICAM-3).

We did not find significant association between T1D and KL-VS alleles. However, we observed that the incidence of KL-VS genotype is lower in a group with retinopathy in comparison to diabetic patients without this complication. Moreover, we established that KL-VS carriers had the lowest levels of inflammatory markers, pro-angiogenic factors and adhesion molecules. Simultaneously, the KL-VS carriers had increased serum levels of anti-inflammatory and anti-angiogenic cytokines than holders bearing wild type genotype.

In conclusion, the findings of our studies suggest that the functional KL-VS variant of the KLOTHO gene protects against the development of retinopathy in patients with T1D.

Klotho is a newly discovered protein that presumably has an important role in the aging process. The goal of this research is to compare the levels of Klotho and Endothelin-1 (ET-1) in the serum and aqueous humor of patients with pseudoexfoliation syndrome (PES) and pseudoexfoliative glaucoma (PEG).

Aqueous humor and serum samples were obtained at the time of cataract surgery from 15 patients with PES, 15 patients with PEG, and 15 control patients. All of the samples were analyzed using enzyme-linked immunosorbent assay to evaluate the levels of ET-1 and Klotho protein.

Aqueous and serum levels of Klotho in PES patients (49.02±10.97, 56.32±10.25 ng/mL) and PEG patients (34.53±4.87, 50.49±2.63 ng/mL) were lower than in control patients (56.31±7.68, 65.06±12.32 ng/mL). Both aqueous and serum levels of Klotho in the PEG group were lower than in the PES group (P=0.001). Mean aqueous and serum levels of ET-1 in the PES (1.28±0.09, 1.65±0.75 pg/mL) and the PEG groups (1.45±0.07, 1.58±0.58 pg/mL) were significantly higher than that measured in the control group (1.17±0.09, 1.16±0.34 pg/mL). Aqueous levels of ET-1 in the PEG group were higher than the PES group (P=0.04), but there were no significant difference in serum levels of ET-1 between the PES and the PEG groups (P=0.83).

Aqueous and serum levels of Klotho decreased both in PES and PEG patients, and this decrease in the PEG group was more significant. In contrast, aqueous and serum levels of ET-1 increased in the PES and the PEG patients, and the increase in the aqueous level of ET-1 in PEG patients was more significant.

Patients with type 1 diabetes and microalbuminuria are at high risk of cardiovascular disease (CVD) and end-stage renal disease. Soluble Klotho is an anti-ageing circulating hormone involved in phosphate metabolism and vascular homeostasis through protective effects on the endothelium and antioxidant actions. The role of soluble Klotho in patients with type 1 diabetes and microalbuminuria is unknown.

In a cross-sectional single-centre study we evaluated the levels of circulating serum soluble Klotho in 33 participants with type 1 diabetes and a history of microalbuminuria (receiving renin-angiotensin system [RAS] inhibitors) and 45 participants with type 1 diabetes without a history of microalbuminuria (not receiving RAS or other antihypertensive drugs). All participants had an eGFR >45 ml/min, duration of diabetes >20 years and no history of CVD. Serum soluble Klotho levels were measured by a validated immunoassay.

Participants with microalbuminuria had significantly lower levels of serum Klotho compared with those without microalbuminuria (median [interquartile range], 659.3 [525.3, 827.6] vs 787.7 [629.5, 1007]; p = 0.023). This difference persisted after adjustment for variables including age and eGFR. In a subgroup of 30 individuals with and without microalbuminuria, other markers of phosphate balance were not significantly different.

In individuals with type 1 diabetes, microalbuminuria is associated with soluble Klotho deficiency. Further studies are required to determine whether soluble Klotho is causally related to the development of cardio-renal disease in type 1 diabetes.

Chronic kidney disease (CKD) patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifications affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho deficiency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, promotes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic inflammation and vascular calcification is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular calcification and the different medications and medical procedures that can help to prolong the survival of CKD patients.

Klotho protein is a β-glucuronidase capable of hydrolyzing steroid β-glucuronides. Two molecules are produced by the Klotho gene, a membrane bound form and a circulating form. This protein is recognized as an antiaging gene with pleiotropic functions. The activation of cellular systems is associated with the pathogenesis of several chronic and degenerative diseases associated with an inflammatory state. Inflammation is characterized by an activation of NFκB. Klotho suppresses nuclear factor NFκB activation and the subsequent transcription of proinflammatory genes. This review focuses on the current understanding of Klotho protein function and its relationship with NFκB regulation, emphasizing its potential involvement in the pathophysiologic process.

Chronic kidney disease (CKD) is the most common metabolic disease of domesticated cats, with most affected cats being geriatric (>12 years of age). The prevalence of CKD in cats exceeds that observed in dogs, and the frequency of the diagnosis of CKD in cats has increased in recent decades. Typical histologic features include interstitial inflammation, tubular atrophy, and fibrosis with secondary glomerulosclerosis. In contrast to people and dogs, primary glomerulopathies with marked proteinuria are remarkably rare findings in cats. Although a variety of primary renal diseases have been implicated, the disease is idiopathic in most cats. Tubulointerstitial changes, including fibrosis, are present in the early stages of feline CKD and become more severe in advanced disease. A variety of factors-including aging, ischemia, comorbid conditions, phosphorus overload, and routine vaccinations-have been implicated as factors that could contribute to the initiation of this disease in affected cats. Factors that are related to progression of established CKD, which occurs in some but not all cats, include dietary phosphorus intake, magnitude of proteinuria, and anemia. Renal fibrosis, a common histologic feature of aged feline kidneys, interferes with the normal relationship between peritubular capillaries and renal tubules. Experimentally, renal ischemia results in morphologic changes similar to those observed in spontaneous CKD. Renal hypoxia, perhaps episodic, may play a role in the initiation and progression of this disease.

Data on serum soluble Klotho levels in chronic kidney disease are contradictory and even less is known after renal transplantation. Experimental studies demonstrated that recombinant human erythropoietin (rhEPO) treatment mitigates Klotho reduction caused by renal damage. Therefore, this study aimed to determine serum Klotho levels in a cohort of kidney transplant recipients (KTR) and to evaluate whether rhEPO treatment can modulate, in vivo and in vitro, soluble Klotho.

117 KTR and 22 healthy subjects (HS) were enrolled. In 17 KTR, rhEPO was discontinued for 5 weeks and Klotho levels were compared to 34 propensity score-matched controls. Moreover, we evaluated Klotho mRNA expression and protein secretion in HK-2 tubular cells treated with cyclosporin A (CyA) and rhEPO, alone or in combination.

Serum Klotho levels in KTR were significantly higher than in HS (0.68 vs. 0.37, p = 0.002) and significantly associated with estimated glomerular filtration rate (r = -0.378, p = 0.003) and fibroblast growth factor 23 (r = -0.307, p < 0.0001). After 5 weeks of rhEPO discontinuation, treated KTR showed a sharper reduction of Klotho levels than controls (-0.56 vs. -0.11 ng/ml, p < 0.0001). In HK-2 cells CyA treatment induced a Klotho down-regulation that was mitigated by rhEPO pre-treatment. In the same experimental conditions, our results revealed that cells treated with CyA + rhEPO secreted higher soluble Klotho levels than those exposed to CyA or rhEPO alone.

Our results demonstrate that KTR have higher serum Klotho levels than HS and that rhEPO treatment modulates these concentrations, suggesting a link between rhEPO and soluble Klotho in KTR.

Klotho deficiency results in excessive formation of 1,25(OH)2D3, accelerated ageing and early death. Moreover, klotho deficiency enhances eryptosis, the suicidal erythrocyte death characterized by phosphatidylserine exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)]i), glucose depletion, hyperosmotic shock and oxidative stress. Klotho expression is decreased and 1,25(OH)2D3-formation enhanced by dehydration. The present study thus explored whether dehydration influences eryptosis.

Blood was drawn from hydrated or 36h dehydrated mice. Plasma osmolarity was determined by vapour pressure method, plasma 1,25(OH)2D3 and aldosterone concentrations using ELISA, and plasma Ca(2+)-concentration utilizing photometry. Erythrocytes were exposed to Ca(2+)-ionophore ionomycin (1 µM, 30 min), energy depletion (12 h glucose removal), hyperosmotic shock (500 mM sucrose added, 2 h) and oxidative stress (100 µM tert-butyl-hydroperoxide, 30 min) and phosphatidylserine exposure at the erythrocyte surface estimated from annexin V binding.

Dehydration increased plasma osmolarity and plasma 1,25(OH)2D3 and aldosterone concentrations. Dehydration did not significantly modify phosphatidylserine-exposure of freshly drawn erythrocytes but significantly enhanced the increase of phosphatidylserine-exposure under control conditions and following treatment with ionomycin, glucose-deprivation, hyperosmolarity or tert-butyl-hydroperoxide.

Dehydration sensitizes the erythrocytes to spontaneous eryptosis and to the triggering of eryptosis by excessive Ca(2+)-entry, energy depletion, hyperosmotic shock and oxidative stress.

Lithium, an inhibitor of glycogen synthase kinase 3 (GSK3), is widely used for the treatment of mood disorders. Side effects of lithium include nephrogenic diabetes insipidus, leading to renal water loss. Dehydration has in turn been shown to downregulate Klotho, which is required as co-receptor for the downregulation of 1,25(OH)2D3 formation by fibroblast growth factor 23 (FGF23). FGF23 decreases and 1,25(OH)2D3 stimulates renal tubular phosphate reabsorption. The present study explored whether lithium influences renal Klotho expression, FGF23 serum levels, 1,25(OH)2D3 formation, and renal phosphate excretion. To this end, mice were analyzed after a 14-day period of sham treatment or of treatment with lithium (200 mg/kg/day subcutaneously). Serum antidiuretic hormone (ADH), FGF23, and 1,25(OH)2D3 concentrations were determined by ELISA or EIA, renal Klotho protein abundance and GSK3 phosphorylation were analyzed by Western blotting, and serum phosphate and calcium concentration by photometry. Lithium treatment significantly increased renal GSK3 phosphorylation, enhanced serum ADH and FGF23 concentrations, downregulated renal Klotho expression, stimulated renal calcium and phosphate excretion, and decreased serum 1,25(OH)2D3 and phosphate concentrations. In conclusion, lithium treatment upregulates FGF23 formation, an effect paralleled by substantial decrease of serum 1,25(OH)2D3, and phosphate concentrations and thus possibly affecting tissue calcification.

Soluble Klotho is an anti-aging phosphaturic protein associated with vascular-renal protection. In vitro and in vivo studies have demonstrated that renin-angiotensin system (RAS) blockade increases soluble Klotho levels. The effect of RAS blockers on soluble Klotho in patients with diabetic kidney disease (DKD) is unknown.

Plasma-soluble Klotho was measured in a secondary analysis of a randomized controlled clinical trial performed at a single university hospital center (ClinicalTrials.gov number NCT001715, from March 2003 to September 2006). Seventy-six patients with type 2 diabetes and DKD (all with albuminuria and serum creatinine <1.7 mg/dl) were studied at baseline and at 24 weeks (study end) after randomization to valsartan/hydrochlorothiazide (n=37) or amlodipine (n=39) treatment. Aortic-pulse wave velocity by applanation tonometry and albuminuria (from three timed urine collections) were also measured at baseline and 24 weeks.

Valsartan/hydrochlorothiazide treatment significantly increased mean (± SD) soluble Klotho (from 432.7 ± 179 to 506.4 ± 226.8 pg/ml; P=0.01) and reduced serum phosphate (from 3.25 ± 1.18 to 2.60 ± 0.96 mg/dl; P=0.04) compared with amlodipine (from 430.1 ± 145.8 to 411.9 ± 157.6 pg/ml and from 2.94 ± 0.56 to 2.69 ± 1.52 mg/dl, respectively). There was a significant difference between treatment groups in soluble Klotho (mean 91.9 pg/ml; 95% confidence interval, 19.9 to 162) and serum phosphate levels (mean -0.68 mg/dl; 95% confidence interval, -0.15 to -1.33) with valsartan/hydrochlorothiazide treatment (P=0.03 and P=0.04, respectively). Attained BP was similar in the two groups and levels of soluble Klotho were not associated with aortic-pulse wave velocity and albuminuria, variables that fell significantly only with valsartan/hydrochlorothiazide.

Treatment with a RAS blocker, valsartan, is associated with an increase in soluble Klotho, which may contribute to the BP-independent cardiorenal benefits of these drugs in DKD.

Aging is a multifactorial process characterized by a progressive decline in physiological function. Decreased kidney function is associated with cardiovascular disease and mortality. Therefore, increasing our insight into kidney aging by understanding the anatomic, physiologic, and pathologic changes of aging in the kidney is important to prevent disastrous outcomes in elderly people.

Male two-, 12-, and 24-month-old C57/BL6 mice were used in this study. We measured histological change, oxidative stress, and aging-related protein expression in the kidneys.

Twenty-four-month-old mice displayed increased albuminuria. Creatinine clearance decreased with aging, although this was not statistically significant. There were increases in mesangial volume and tubulointerstitial fibrosis in 24-month-old mice. There were also increases in F4/80 expression and in apoptosis detected by TUNEL assay. Urine isoprostane excretion increased with aging and SOD1 and SOD2 were decreased in 24-month-old mice. Oxidative stress may be mediated by a decrease in Sirt1, PGC-1α, ERR-1α, and PPARα expression. Klotho expression also decreased.

Our results demonstrate that Sirt1 was decreased with aging and may relate to changed target molecules including PGC-1α/ERR-1α signaling and PPARα. Klotho can also induce oxidative stress. Pharmacologically targeting these signaling molecules may reduce the pathologic changes of aging in the kidney.