Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Abstract

Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was Ϸ30% in ICGN mice, and Ϸ70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in ␤-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.aging ͉ glomerulonephritis ͉ oxidative stress ͉ tubular interstitial disease T he Klotho gene was originally identified by insertional mutagenesis, and it encodes a 130-kDa transmembrane protein that shares sequence homology with ␤-glucosidase (1). The gene is predominantly expressed in the kidney and, to a lesser extent, in the brain and reproductive and endocrine organs. Its deletion in mice (Kl Ϫ/Ϫ ) results in the development of a syndrome resembling human aging, including shortened life span, growth retardation, infertility, arteriosclerosis, skin and muscle atrophy, osteoporosis, and pulmonary emphysema (1). Conversely, overexpression of the Klotho gene extends the life span in mice (2). Although kl Ϫ/Ϫ mice do not show any overt renal abnormalities, the Klotho mRNA expression in the kidneys has been shown to be greatly reduced in patients with chronic renal failure (3). Notably, most of the features of Klotho gene-deleted mice are similar to those of the patients with chronic renal failure. In addition, Klotho gene expression has been found to be reduced in acute renal failure in ischemia-reperfusion injury murine models (4). These findings would imply that the reduction of Klotho protein may be relevant to the pathophysiology of renal failure. However, little is known concerning whether Klotho protein itself could exert an ameliorative effect on a diseased kidney to preserve its renal functions and thus could serve as a therapeutic target in various ...

The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

“…However we can speculate on a nephroprotective role of Klotho based on the beneficial effect of Klotho overexpression on progressive renal injury 55 and in AKI. 42,56 In summary, the inflammatory cytokines TWEAK and TNF␣ downregulate Klotho in renal tubular cells through an NFBdependent mechanism.…”

“…44,45 Locally, a reduction of Klotho expression contributed to progression of kidney failure; although its overexpression ameliorated renal injury in a mouse model. 46 Ad-Klotho gene transfer improved serum creatinine and reduced renal apoptosis induced by ischemia-reperfusion in rats. 22 Klotho transfection reduced H 2 O 2 -induced tubular cell apoptosis in culture.…”

Renal Production, Uptake, and Handling of Circulating αKlotho

“…aKlotho is found in urine and serum of rodents and humans 2,20,42,56 ; and the kidney has the highest abundance of aKlotho compared with other organs. Clinical and experimental animal studies showed low renal tubular aKlotho expression in both acute kidney injury and CKD 10,40,42,43,[56][57][58][59][60][61][62] and low circulating aKlotho levels in kidney diseases of a variety of etiologies in animals 42,43,56,62 and humans. 32,44,61,63 These data suggest that the kidney contributes to circulating aKlotho.…”

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

“…Recent work has shown that plasma and urine levels of soluble Klotho are significantly elevated in DM patients with relatively preserved renal function compared to control subjects. Hence, in DN, Klotho expression levels were decreased in kidneys of patients with early DN but with increased levels of plasma and urinary Klotho, and that Klotho deficiency may serve as a biomarker as well as a pathogenic factor for the progression of renal disease and further complications [39][40][41].…”