Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

Pofi, Riccardo; Fiore, Daniela; Gaetano, Rita De; Panio, Giuseppe; Gianfrilli, Daniele; Pozza, Carlotta; Barbagallo, Federica; Xiang, Yang; Giannakakis, Konstantinos; Lenzi, Andrea; Naro, Fabio; Isidori, Andrea M.; Venneri, Mary Anna

doi:10.1038/srep44584

Cited by 33 publications

(33 citation statements)

References 52 publications

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“…In experimental studies, the adaptation of renal RI to facilitate detailed renal injury has been limited, primarily because of technical difficulties in imaging mice versus humans, including the small size of mice, the high heart rates of small animals, and the high speed for data acquisition and storage. However, recently developed imaging techniques allow us to obtain high-frequency and high-resolution images with ultrasound to monitor blood flow and analyze RI values in the tiny vessel [21]. Accordingly, we observed that RI levels were increased in the early stage of HFD-feeding, and they continued to increase with long-term HFD-feeding.…”

Section: Discussionsupporting

confidence: 50%

Renal Resistive Index as a Novel Indicator for Renal Complications in High-Fat Diet-Fed Mice

Lü

et al. 2017

Kidney Blood Press Res

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Background/Aims: The renal resistive index (RI) is a novel candidate as a renal injury prognostic indicator, but it remains unclear how renal RI levels correspond to renal injury in diabetic nephropathy. Methods: To examine this issue, we compared 8-week-old male C57BL/6 mice fed with high-fat diet (HFD) versus chow diet (CHD) for 16 weeks. At 8 and 12 weeks, the glomerular filtration rate (GFR), urinary albumin-to-creatinine ratio (UACR), and inflammatory factors (IL-1β, IL-6, TNFα, and MCP-1) were measured, along with the increase in renal RI. Results: Our study suggests RI values positively correlate with GFR for the first 12 weeks of HFD feeding. In contrast, the GFR of 16-week HFD feeding is lower than that of 12-week HFD feeding, whereas RI levels are significantly increased. Additionally, our study suggests RI values accurately indicate the renal fibrosis and renal injury in HFD-fed mice treated with lovastatin. Conclusion: This study seems to confirm the utility of a noninvasive and repeatable ultrasound parameter to rapidly evaluate renal fibrosis in a HFD-induced type 2 diabetic mouse model in vivo. This highly sensitive and comparable renal RI measurement could monitor the whole procedure of disease development in real-time. RI measurement of the renal artery is capable of differentiating responses to standard therapy with lovastatin in HFD-fed mice from the CHD group.

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Section: Discussionsupporting

confidence: 50%

Renal Resistive Index as a Novel Indicator for Renal Complications in High-Fat Diet-Fed Mice

Lü

et al. 2017

Kidney Blood Press Res

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“…Furthermore, miR-22 selected by NGS analysis was also decreased in the UExo of KD compared to that of NR cats. Altered miR-22 expression was reported in several KDs, and it was upregulated in the kidney of diabetic mice ( 29 ) and rhabdomyolysis-induced acute kidney injury (AKI) mice ( 30 ) but downregulated in human renal cell carcinoma ( 31 ). Further, miR-22 regulates the synthesis of collagen IV and α-smooth muscle actin in tubulointerstitial fibrosis by targeting phosphatase and tensin homolog (PTEN) ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Urinary Exosome-Derived microRNAs Reflecting the Changes in Renal Function in Cats

et al. 2018

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Increased incidence of kidney disease (KD) is a common concern in human and companion animals. Cats, in particular, are highly susceptible to KD. Novel KD biomarkers would help to address these problems. Therefore, we are focusing on microRNA, a highly conserved nucleic acid, as a KD biomarker for various animals. We previously reported that altered levels of urinary exosome (UExo)-derived microRNAs indicate renal pathologies in dogs. This study comprehensively examined UExo-derived microRNAs, which reflected the KD status in cats. The examined cats were divided into two groups: normal renal function (NR) and KD. Based on our previous data in dogs and cats, as well as the present data on UExo-derived microRNAs in cats by next-generation sequencing, let-7b, let-7f, miR-10a, miR-10b, miR-21a, miR-22, miR-26a, miR-27b, miR-146a, miR-181a, miR-191, and miR-486a were identified as biomarker candidates. In summary, the levels of UExo-derived let-7b, miR-22, and miR-26a significantly decreased in cats with KD from the early stages of the disease. UExo-derived miRNA levels normalized to urinary creatinine or total RNA of miR-21a was significantly higher in the KD group. Importantly, the ratio of UExo-derived miR-21a to let-7b showed a significant and strongest correlation with serum creatinine (ρ = 0.751), blood urea nitrogen (ρ = 0.754), and urinary creatinine (ρ = −0.421) among all examined indices. Further, the ratio of miR-181a to let-7b or miR-10b significantly correlated with the progression of renal dysfunction in the KD group. Thus, we identified that UExo-derived microRNAs in cats, and their raw and normalized levels could indicate altered renal function.

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“…However, the application of resistivity and pulsatility indexes to the exploration of mechanisms of renal vascular dysfunction in preclinical models has been limited [ 7 , 9 ]. In this study, we utilized a novel non-invasive ultrasound technique to evaluate indices of kidney microvascular health (RRI and PI) in a preclinical model of diabetic nephropathy, as has been previously reported [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury

Aroor

Das

Carpenter

et al. 2018

Cardiovasc Diabetol

134

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BackgroundArterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db).Materials/methodsTen-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg−1 day−1, and fed for 5 weeks, initiated at 11 weeks of age.ResultsCompared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of “reversion inducing cysteine rich protein with Kazal motifs” (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells.ConclusionsEmpagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.

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Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

Cited by 33 publications

References 52 publications

Renal Resistive Index as a Novel Indicator for Renal Complications in High-Fat Diet-Fed Mice

Renal Resistive Index as a Novel Indicator for Renal Complications in High-Fat Diet-Fed Mice

Urinary Exosome-Derived microRNAs Reflecting the Changes in Renal Function in Cats

Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury

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