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. 2022 Jul 24;23(15):8150.
doi: 10.3390/ijms23158150.

Fluorescence Imaging Using Enzyme-Activatable Probes for Detecting Diabetic Kidney Disease and Glomerular Diseases

Kentaro Yamada  1 , Tomoaki Takata  1 , Takuji Iyama  1 , Shintaro Hamada  1 , Yukari Mae  1 , Takaaki Sugihara  1 , Hajime Isomoto  1
Affiliations

Fluorescence Imaging Using Enzyme-Activatable Probes for Detecting Diabetic Kidney Disease and Glomerular Diseases

Kentaro Yamada et al. Int J Mol Sci. .

Abstract

A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it has the risk for potential complications. Here, we aimed to investigate the feasibility of urinary fluorescence imaging using an enzyme-activatable probe for differentiating diabetic kidney disease and the other glomerular diseases. Hydroxymethyl rhodamine green (HMRG)-based fluorescent probes targeting gamma-glutamyl transpeptidase (GGT) and dipeptidyl-peptidase (DPP) were used. Urinary fluorescence was compared between groups which were classified by their histopathological diagnoses (diabetic kidney disease, glomerulonephritis, and nephrosclerosis) as obtained by ultrasound-guided renal biopsy. Urinary fluorescence was significantly stronger in patients with diabetic kidney disease compared to those with glomerulonephritis/nephrosclerosis after DPP-HMRG, whereas it was stronger in patients with nephrosclerosis than in patients with glomerulonephritis after GGT-HMRG. Subgroup analyses of the fluorescence performed for patients with diabetes showed consistent results. Urinary fluorescence imaging using enzyme-activatable fluorescence probes thus represents a potential noninvasive assessment technique for kidney diseases in patients with diabetes.

Keywords: diabetic kidney disease; diabetic nephropathy; dipeptidyl-peptidase; enzyme-activatable probe; fluorescence imaging; fluorescent probe; gamma-glutamyl transpeptidase; glomerulonephritis; nephrosclerosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Urinary fluorescence analysis. (a,b) Scheme of fluorescence imaging using enzyme-activatable fluorescent probes. GGT-HMRG and DPP-HMRG are non-fluorescent but emit fluorescence upon activation by GGT or DPP. (c) Representative urinary fluorescence images after DPP-HMRG and GGT-HMRG. Although the urine showed a faint autofluorescence, remarkable fluorescence was observed after incubation with the fluorescent probes.
Figure 2
Figure 2
Fluorescence images of urine after incubation with DPP-HMRG. Representative fluorescence images of urine obtained from patients with diabetic kidney disease (a), glomerulonephritis (b), and nephrosclerosis (c) after incubation with DPP-HMRG. Urine from patients with diabetic kidney disease showed a significantly high fluorescence intensity compared to the other groups (d). * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Fluorescence images of urine after incubation with GGT-HMRG. Representative fluorescence images of urine obtained from patients with diabetic kidney disease (a), glomerulonephritis (b), and nephrosclerosis (c) after incubation with GGT-HMRG. Urine from patients with nephrosclerosis showed a significantly high fluorescent intensity than those with glomerulonephritis (d). * p < 0.05.
Figure 4
Figure 4
Fluorescent intensities of urine in patients with diabetes. Urinary fluorescent intensities after incubation with DPP-HMRG (a) and GGT-HMRG (b) in patient with diabetes. Diabetic kidney disease could be distinguished from the other groups by DPP-HMRG, whereas nephrosclerosis could be differentiated from glomerulonephritis by GGT-HMRG. * p < 0.05.
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