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Aging and disease
Orginal Article |
Renoprotective Effect of a Dipeptidyl Peptidase-4 Inhibitor on Aging Mice
Tae H. Ban, Eun N. Kim, Min Y. Kim, Ji H. Lim, Jong H. Lee, Hyung D. Kim, Hye E. Yoon, Cheol W. Park, Bum S. Choi*
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Abstract  

Dipeptidyl peptidase 4 (DPP-4) inhibitors exert pleiotropic effects beyond glycemic control. We investigated the renoprotective effects of DPP-4 inhibitors on aging mice mediated by the renin-angiotensin system (RAS). C57BL/6 mice were divided into three groups: the two-month-old mice (YM group), the eighteen-month-old mice (AM group) and the eighteen-month-old, linagliptin-treated mice (AM + LIN group). Renal function was improved, based on serum creatinine and cystatin-C levels (p < 0.05 compared with the AM group for both parameters). Fibrotic areas and the levels of proteins related to fibrosis improved in the AM + LIN group (p < 0.001 compared with the AM group for all parameters). In the AM + LIN group, the DPP-4-positive area and activity and expressions of DPP-4 were decreased (p < 0.05 compared with the AM group for all parameters). The levels of proteins related to the RAS, including prorenin receptor, angiotensin-converting enzyme, angiotensin II and angiotensin 1 receptor, were decreased in the AM + LIN group (p < 0.05, p < 0.01, p < 0.05, and p < 0.01 compared with the AM group, respectively). NADPH oxidase 2 and NADPH oxidase 4 levels decreased in the AM + LIN group (p < 0.001 compared with the AM group for both proteins), whereas the levels of endothelial nitric oxide synthase (eNOS) phosphorylated at serine1177 and superoxide dismutase 1 were increased (p < 0.01 compared with the AM group for both proteins). DPP-4 inhibitors may exert renoprotective effects via prorenin receptor/angiotensin-converting enzyme/angiotensin II/angiotensin 1 receptor axis.

Keywords aging kidney      aging      renin-angiotensin system      dipeptidyl peptidase 4      renoprotective effect     
Corresponding Authors: Bum S. Choi   
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These authors contributed equally to this work.

Just Accepted Date: 09 August 2019  
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Tae H. Ban
Eun N. Kim
Min Y. Kim
Ji H. Lim
Jong H. Lee
Hyung D. Kim
Hye E. Yoon
Cheol W. Park
Bum S. Choi
Cite this article:   
Tae H. Ban,Eun N. Kim,Min Y. Kim, et al. Renoprotective Effect of a Dipeptidyl Peptidase-4 Inhibitor on Aging Mice[J]. Aging and disease, 10.14336/AD.2019.0620
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http://www.aginganddisease.org/EN/10.14336/AD.2019.0620     OR     http://www.aginganddisease.org/EN/Y/V/I/0
Figure 1.  Effects of linagliptin on renal function and aging-related renal injury histology. (A) Serum creatinine levels were increased in the AM group compared to the AM group (p < 0.001), and decreased in the AM + LIN group compared to the AM group (p < 0.05). (B) Albuminuria was increased in the AM group, but it was not different in the AM and AM + LIN groups. (C) Creatinine clearance was decreased in the AM group, but it was similar in the AM and AM + LIN groups. (D) Serum cystatin-C levels were increased in the AM group compared to the AM group (p < 0.001) and decreased in the AM + LIN group compared to the AM group (p < 0.05). (E) The expansion of the mesangial area of PAS-stained kidneys was significantly reduced in the AM + LIN group (original magnification ×400). (F) Decreased tubulointerstitial fibrosis was observed in Masson’s trichrome-stained kidney sections from the AM + LIN group (original magnification ×400). (G) The areas of extracellular matrix in the glomerulus and (H) the areas of tubulointerstitial fibrosis determined using a quantitative assessment were definitely decreased in the AM + LIN group (p < 0.001 for both). (*p < 0.05 and ‡p < 0.001).
Figure 2.  Effects of linagliptin on fibrosis and inflammation in renal tissue. (A) The numbers of collagen IV-, (B) TGF-β- and (C) MCP-1-positive cells were decreased in the AM + LIN group compared to the AM group. (D), (E) and (F) The areas positive for collagen IV, TGF-β and MCP-1 were markedly increased in the AM + LIN group. (G) Levels of markers fibrosis and inflammation were analyzed using western blotting. (H) and (I) Comparison of fibronectin and collagen IV levels between the three groups. (J) and (K) Comparison of TGF-β and CTGF levels between the three groups. (*p < 0.05, †p < 0.01, and ‡p < 0.001).
Figure 3.  Effects of linagliptin on DPP-4 levels in renal tissues and serum DPP-4 activity. (A) Representative images of immunohistochemical staining for DPP-4 showing positively stained areas in the renal tissue. (B) The DPP-4-positive area was markedly decreased in the AM + LIN group compared with the AM group (‡p < 0.001). (C) Representative western blots showing DPP-4 levels in the renal tissue. (D) Lower levels of the DPP-4 protein were detected in the AM + LIN group than in the AM group (p < 0.05) (E) Lower DPP-4 activity was observed in the AM + LIN group than in the AM group (p < 0.05). (F) The serum DPP-4 activity was increased in the AM group compared with the YM group (p < 0.001), but it was not different between the AM group and the AM + LIN group. (*p < 0.05 and ‡p < 0.001).
Figure 4.  Effects of linagliptin on angiotensin II levels and PRR, ACE and AT1R protein expression in kidneys. (A) The levels of Ang II in the kidneys were decreased in the AM + LIN group compared with the AM group (p < 0.05). (B) Representative western blots of PRR, ACE and AT1R protein expression. (C) Lower levels of the PRR protein were detected in the AM + LIN group than in the AM group (p < 0.05). (D) Lower levels of the ACE protein were observed in the AM + LIN group than in the AM group (p < 0.01). (E) Lower levels of the AT1R protein were observed in the AM + LIN group than in the AM group (p < 0.01). (*p < 0.05, †p < 0.01, and ‡p < 0.001).
Figure 5.  Effects of linagliptin on angiotensin (1-7) concentrations and ACEII, AT2R and MasR protein expression in kidneys. (A) Representative western blots of ACEII, AT2R and MasR protein expression. (B), (C) and (D) Levels of the ACEII, AT2R and MasR proteins were decreased in the AM group compared to the YM group (p < 0.05 for all), but the levels were similar in the AM and AM + LIN groups. (E) Lower levels of Ang (1-7) were detected in the kidneys from the AM group than in the YM group (p < 0.001), but similar levels were observed in the AM and AM+LIN groups. (*p < 0.05 and ‡p < 0.001).
Figure 6.  Effects of linagliptin on phospho-Ser1177eNOS/eNOS, NOX2 and NOX4 in renal tissue. (A) Representative western blots of phospho-Ser1177eNOS/eNOS expression. (B) The ratio of phospho-Ser1177 eNOS/eNOS was significantly increased in the AM + LIN group (p < 0.05). (C) Representative western blots of Nox2 and Nox4 levels. (D) Nox2 levels were decreased in the AM + LIN group compared with the AM group (p < 0.001). (E) Nox4 levels were significantly decreased in the AM + LIN group (p < 0.001). (*p < 0.05, †p < 0.01, and ‡p < 0.001).
Figure 7.  Effects of linagliptin on SOD1 and SOD2 in renal tissue. (A) Representative western blots of SOD1 and SOD2 levels. (B) SOD1 levels were increased in the AM + LIN group compared with the AM group (p < 0.01). (C) SOD2 levels were decreased in the AM group compared to the YM group (p < 0.05), but the levels were not significantly different between the AM group and the AM + LIN group. (*p < 0.05 and †p < 0.01).
Figure 8.  Effects of linagliptin on renal tubular cell injury in HRPTEpiCs. (A) The Ang II-treated group showed an increased number of SA β-gal-positive cells compared to the Cont group. Treatment with LIN decreased the number of SA β-gal-positive cells in the Ang II group, whereas LIN treatment did not affect that in the Cont group. (B) Representative western blots of expression of the renin-angiotensin system in HRPTEpiCs. (C) and (D) Ang II increased the expression of ACE and AT1R compared to the control (p < 0.05 for both), but those effects diminished after adding linagliptin to the Ang II-treated cells (p < 0.01 and p < 0.05, respectively). (E) and (F) The expression levels of AT2R and MasR in the Ang II groups were not different regardless of LIN treatment. (G) Representative western blots of expression of the markers of anti-inflammatory and antioxidant systems in HRPTEpiCs. (H) and (I) The levels of fibronectin and collagen IV were increased in HRPTEpiCs treated with Ang II (p < 0.05 and p < 0.001, respectively), but those effects were stabilized after the administration of linagliptin to Ang II-treated cells (p < 0.05 and p < 0.01, respectively). (J) and (K) The expression levels of SOD1 and SOD2 were not significantly changed in HRPTEpiCs treated with Ang II. The expression of SOD1 improved after adding linagliptin to Ang II-treated cells (p < 0.05), but the expression of SOD2 did not change even after the addition of linagliptin. (L) Representative western blots showing decreased levels of DPP-4 and AT1R in HRPTEpiCs transfected with siRNAs targeting DPP-4. (M) and (N) DPP-4 and AT1R levels were significantly decreased in cells transfected with the siRNA targeting DPP-4 (p < 0.001 and p < 0.05, respectively). (*p < 0.05, †p < 0.01, and ‡p < 0.001).
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