Pathophysiology of the aging kidney and therapeutic interventions

Kanasaki, Keizo; Kitada, Munehiro; Koya, Daisuke

doi:10.1038/hr.2012.159

Cited by 43 publications

(31 citation statements)

References 138 publications

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“…Renal fibrosis, the final common pathway of progressive kidney diseases, disrupts kidney structure and thus reduces the organ's filtration function [74][75][76][77][78][79]. The two main loci for renal fibrosis are the tubulointerstitial space and the glomerulus.…”

Section: Antifibrotic Effectsmentioning

confidence: 99%

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Kanasaki

2018

Clinical Science

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Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

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Section: Antifibrotic Effectsmentioning

confidence: 99%

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Kanasaki

2018

Clinical Science

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“…One of the most successful interventional measures that have been shown to slow down and delay age-related kidney disease is caloric restriction (16)(17)(18)(19)(20). Studies in our lab have demonstrated that caloric restriction prevents age-related kidney disease in part by preventing the increased expression of the sterol regulatory element binding proteins SREBP-1 and SREBP-2 that are master regulators of fatty acid, triglyceride and cholesterol synthesis (16,17) .…”

Section: Fxr-tgr5 Reverses Age-related Kidney Diseasementioning

confidence: 97%

A dual agonist of farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice

Wang

Luo

Wang

et al. 2017

Journal of Biological Chemistry

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Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid-activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates. We therefore determined the effects of aging and caloric restriction on the expression of FXR and TGR5 in the kidney. We found that FXR and TGR5 expression are decreased in the aging kidney, and that caloric restriction prevents these age-related decreases. Interestingly, in long-lived Ames dwarf mice renal FXR and TGR5 expression levels were also increased. A 2-month treatment of 22-month-old C57BL/6J mice with the FXR-TGR5 dual agonist induced caloric restriction-like effects and reversed age-related increases in proteinuria, podocyte injury, fibronectin accumulation, TGF-β expression, and, most notably, age-related impairments in mitochondrial biogenesis and mitochondrial function. Furthermore, in podocytes cultured in serum obtained from old mice, INT-767 prevented the increases in the proinflammatory markers TNF-α, toll-like receptor 2 (TLR2), and TLR4. In summary, our results indicate that FXR and TGR5 may play an important role in modulation of age-related kidney disease.

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“…Fibrosis is the final common pathway of progressive kidney diseases (similar to what occurs in other organs) and results in the destruction of the normal kidney structure and a significant deterioration in kidney function (Risdon et al, 1968; Schainuck et al, 1970; Striker et al, 1970; Mackensen-Haen et al, 1981; Nath, 1992; Kanasaki et al, 2012). Kidney fibrosis is induced by prolonged damage associated with impairment of the normal regulatory mechanisms for wound healing and an accumulation of extracellular matrix (ECM).…”

Section: Introductionmentioning

confidence: 99%

N-acetyl-seryl-aspartyl-lysyl-proline: a valuable endogenous anti-fibrotic peptide for combating kidney fibrosis in diabetes

et al. 2014

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Fibroproliferative diseases are responsible for 45% of deaths in the developed world. Curing organ fibrosis is essential for fibroproliferative diseases. Diabetic nephropathy is a common fibroproliferative disease of the kidney and is associated with multiorgan dysfunction. However, therapy to combat diabetic nephropathy has not yet been established. In this review, we discuss the novel therapeutic possibilities for kidney fibrosis in diabetes focusing on the endogenous anti-fibrotic peptide, N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is the substrate for angiotensin-converting enzyme and exhibits meaningful anti-fibrotic effects in various experimental models of fibrotic disease.

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Pathophysiology of the aging kidney and therapeutic interventions

Cited by 43 publications

References 138 publications

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

A dual agonist of farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice

N-acetyl-seryl-aspartyl-lysyl-proline: a valuable endogenous anti-fibrotic peptide for combating kidney fibrosis in diabetes

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