Pan-Src kinase inhibitor treatment attenuates diabetic kidney injury via inhibition of Fyn kinase-mediated endoplasmic reticulum stress

Dorotea Debra,Jiang Songling,Pak Eun Seon,Son Jung Beom,Choi Hwan Geun,Ahn Sung-Min,Ha Hunjoo 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Src family kinases (SFKs) have been implicated in the pathogenesis of kidney fibrosis. However, the specific mechanism by which SFKs contribute to the progression of diabetic kidney disease (DKD) remains unclear. Our preliminary transcriptome analysis suggested that SFK expression was increased in diabetic kidneys and that the expression of Fyn (a member of the SFKs), along with genes related to unfolded protein responses from the endoplasmic reticulum (ER) stress signaling pathway, was upregulated in the tubules of human diabetic kidneys. Thus, we examined whether SFK-induced ER stress is associated with DKD progression. Mouse proximal tubular (mProx24) cells were transfected with Fyn or Lyn siRNA and exposed to high glucose and palmitate (HG-Pal). Streptozotocin-induced diabetic rats were treated with KF-1607, a novel pan-Src kinase inhibitor (SKI) with low toxicity. The effect of KF-1607 was compared to that of losartan, a standard treatment for patients with DKD. Among the SFK family members, the Fyn and Lyn kinases were upregulated under diabetic stress. HG-Pal induced p70S6 kinase and JNK/CHOP signaling and promoted tubular injury. Fyn knockdown but not Lyn knockdown inhibited this detrimental signaling pathway. In addition, diabetic rats treated with KF-1607 showed improved kidney function and decreased ER stress, inflammation, and fibrosis compared with those treated with losartan. Collectively, these findings indicate that Fyn kinase is a specific member of the SFKs implicated in ER stress activation leading to proximal tubular injury in the diabetic milieu and that pan-SKI treatment attenuates kidney injury in diabetic rats. These data highlight Fyn kinase as a viable target for the development of therapeutic agents for DKD.

A pan-NADPH Oxidase Inhibitor Ameliorates Kidney Injury in Type 1 Diabetic Rats

Dorotea, Debra,Kwon, Guideock,Lee, Jung Hwa,Saunders, Erika,Bae, Yun Soo,Moon, Sung Hwan,Lee, Soo Jin,Cha, Dae Ryong,Ha, Hunjoo S. Karger 2018 Pharmacology Vol. No.

<P><B><I>Background:</I></B> NADPH oxidases (Nox) is a major enzyme system contributing to oxidative stress, which plays an important role in the pathogenesis of diabetic kidney disease (DKD). We have shown an elevation of renal Nox1, Nox2, and Nox4 in diabetic mice. APX-115, a pan-Nox inhibitor, attenuated the progression of DKD in mice. As the standard diabetic mice cannot fully mimic human DKD, the present study was aimed to show the dose-dependent effect and to provide a confirmatory evidence of APX-115 in attenuating DKD in diabetic rats. <B><I>Method:</I></B> Type 1 diabetes was induced by a single 60 mg/kg intraperitoneal injection of streptozotocin in Sprague-Dawley rats. 0.5, 5, or 30 mg APX-115/kg/day or losartan 1 mg/kg/day were administered orally to diabetic rats for 8 weeks. <B><I>Results:</I></B> APX-115 treatment showed an improvement in kidney function and tubular and podocyte ­injury, as well as attenuation of inflammation, fibrosis, and oxidative stress as much as losartan, a comparative drug and mainstay treatment in DKD. Therapeutic effect of APX-115 was exhibited in a dose-dependent manner; a dose of 30 mg/kg displayed a superior efficacy. <B><I>Conclusion:</I></B> This finding verified the pre-clinical data of APX-115 in protecting against DKD, which is important to bring APX-115 toward the next stage of drug development.</P>

Activation of β2 adrenergic receptor signaling modulates inflammation: a target limiting the progression of kidney diseases

Debra Dorotea,하헌주 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.1

Beta 2 adrenergic receptor (β2-AR)-agonists,widely used as bronchodilators, have demonstrated widespectrumanti-inflammatory properties in both immune andnon-immune cells in various tissues. Their anti-inflammatoryproperties are mediated primarily, but not exclusively,via activation of the canonical β2-AR signaling pathway(β2-AR/cAMP/PKA). As non-canonical β2-AR signalingalso occurs, several inconsistent findings on the antiinflammatoryeffect of β2-agonists are notably present. Increasing amounts of evidence have unveiled the alternativemechanisms of the β2-AR agonists in protecting thetissues against injuries, i.e., by augmenting mitochondriabiogenesis and SIRT1 activity, and by attenuating fibroticsignaling. This review mainly covers the basic mechanismsof the anti-inflammatory effects of β2-AR activation alongwith its limitations. Specifically, we summarized the role ofβ2-AR signaling in regulating kidney function and in mediatingthe progression of acute and chronic kidney diseases. Given their versatile protective effects, β2-agonists can be apromising avenue in the treatment of kidney diseases.

Orally active, species-independent novel A3 adenosine receptor antagonist protects against kidney injury in db/db mice

Debra Dorotea,조아름,이가영,권귀덕,이정화,Pramod K. Sahu,정낙신,차대룡,하헌주 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors. Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of adenosine receptors, namely, A1AR, A2aAR, A2bAR, and A3AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A3AR antagonist, LJ-1888, ameliorates unilateral ureteral obstructioninduced tubulointerstitial fibrosis. The present study examined the protective effects of LJ-2698, which has higher affinity and selectivity for A3AR than LJ-1888, on DKD. In experiment I, dose-dependent effects of LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of LJ-2698 (10 mg/kg) were compared to those of losartan (1.5 mg/kg), which is a standard treatment for patients with DKD. LJ-2698 effectively prevented kidney injuries such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, inflammation, and oxidative stress in diabetic mice as much as losartan. In addition, inhibition of lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either LJ-2698 or losartan. These results suggest that LJ-2698, a selective A3AR antagonist, may become a novel therapeutic agent against DKD.

KF-1607, a Novel Pan Src Kinase Inhibitor, Attenuates Obstruction-Induced Tubulointerstitial Fibrosis in Mice

( Debra Dorotea ),( Seungyeon Lee ),( Sun Joo Lee ),( Gayoung Lee ),( Jung Beom Son ),( Hwan Geun Choi ),( Sung-min Ahn ),( Hunjoo Ha ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.1

Src family kinases (SFKs), an important group of non-receptor tyrosine kinases, are suggested to be excessively activated during various types of tissue fibrosis. The present study investigated the effect of KF-1607, an orally active and a newly synthesized Src kinase inhibitor (SKI) with proposed low toxicity, in preventing the progression of renal interstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed in 6-week-old male C57BL/6 mice to induce renal interstitial fibrosis. Either KF-1607 (30 mg/kg, oral gavage) or PP2 (2 mg/kg, intraperitoneal injection), a common experimental SKI, was administered to mice for seven days, started one day prior to surgery. UUO injury-induced SFK expression, including Src, Fyn, and Lyn kinase. SFK inhibition by KF-1607 prevented the progression of tubular injury in UUO mice, as indicated by decreases in albuminuria, urinary KIM-1 excretion, and kidney NGAL protein expression. Renal tubulointerstitial fibrosis was attenuated in response to KF-1607, as shown by decreases in α-SMA, collagen I and IV protein expression, along with reduced Masson’s trichrome and collagen-I staining in kidneys. KF-1607 also inhibited inflammation in the UUO kidney, as exhibited by reductions in F4/80 positive-staining and protein expression of p-NFκB and ICAM. Importantly, the observed effects of KF-1607 were similar to those of PP2. A new pan Src kinase inhibitor, KF-1607, is a potential pharmaceutical agent to prevent the progression of renal interstitial fibrosis.

Fyn Kinase: A Potential Therapeutic Target in Acute Kidney Injury

( Md Jamal Uddin ),( Debra Dorotea ),( Eun Seon Pak ),( Hunjoo Ha ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.3

Acute kidney injury (AKI) is a common disease with a complex pathophysiology which significantly contributes to the development of chronic kidney disease and end stage kidney failure. Preventing AKI can consequently reduce mortality, morbidity, and healthcare burden. However, there are no effective drugs in use for either prevention or treatment of AKI. Developing therapeutic agents with pleiotropic effects covering multiple pathophysiological pathways are likely to be more effective in attenuating AKI. Fyn, a nonreceptor tyrosine kinase, has been acknowledged to integrate multiple injurious stimuli in the kidney. Limited studies have shown increased Fyn transcription level and activation under experimental AKI. Activated Fyn kinase propagates various downstream signaling pathways associated to the progression of AKI, such as oxidative stress, inflammation, endoplasmic reticulum stress, as well as autophagy dysfunction. The versatility of Fyn kinase in mediating various pathophysiological pathways suggests that its inhibition can be a potential strategy in attenuating AKI.

Slide Session : OS-HEM-09 ; Hematology : Prevalence and Mortality of Cardiac Involvement in Patients with Amyloidosis of an Institutional Registry Amyloidosis

( Maria Adela Aguirre ),( Maria Lourdes Posadas Martinez ),( Melisa Blomberg ),( Dorotea Beatriz Fantl ),( Diego Hernan Giunta ),( Fernan Gonzalez Bernaldo De Quiroz ),( Maria Florencia Grande Ratti ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: Cardiac involvement is the leading cause of morbidity and mortality of amy-loidosis, especially due to light-chain (AL) and transthyretin, both wild and hereditary types. Objectives: To estimate the prevalence and mortality of patients with evidence of cardiac involvement in patients diagnosed with amyloidosis. Methods: Ambispective cohort study, with data obtained from all patients included between 01/2007 and 03/2013 with evidence of amyloidosis in the Institutional Regis-try Amyloidosis of the Hospital Italiano de Buenos Aires. The diagnostic criteria of cardiac amyloidosis were predefined. Mortality from cardiac amyloidosis was measured using a combination of active and passive assessment. Survival time was evaluated using the Kaplan-Meier estimator. SPSS 19.0 was used. Results: The registry included 126 patients and the prevalence of cardiac amyloidosis was 40% (95%, CI:31-49%). Among the 40% (50/126) of patients with confirmed amyloidosis and suspected of cardiac involvement, the median age was 72 years (IQR 79-81) and 26% were women (13/50). Suspected diagnosis of cardiac involvement was: clinical 82.4% (42/50), from complementary studies 67% (34/50), and diagnosed from another hospital 6% (3/50). From all patients with suspected cardiac involvement, 47% had con- firmed biopsy. Overall mortality of patients with cardiac involvement was 20% (11/50), the median survival was 1782 days of follow up (CI 95% 1365-2199). Conclusions: The prevalence of cardiac involvement and mortality in patients with amyloidosis was high. Advances in diagnosis of the possible causes of amyloidosis in the future will allow the detection of patients with high risk of death from cardiac causes in our country.

Peroxisomal Fitness: A Potential Protective Mechanism of Fenofibrate against High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice

JIANG SONGLING,UDDIN MD JAMAL,Xiaoying Yu,Lingjuan Piao,Dorotea Debra,Oh Goo Taeg,Ha Hunjoo 대한당뇨병학회 2022 Diabetes and Metabolism Journal Vol.46 No.6

Background: Non-alcoholic fatty liver disease (NAFLD) has been increasing in association with the epidemic of obesity and diabetes. Peroxisomes are single membrane-enclosed organelles that play a role in the metabolism of lipid and reactive oxygen species. The present study examined the role of peroxisomes in high-fat diet (HFD)-induced NAFLD using fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist.Methods: Eight-week-old male C57BL/6J mice were fed either a normal diet or HFD for 12 weeks, and fenofibrate (50 mg/kg/day) was orally administered along with the initiation of HFD.Results: HFD-induced liver injury as measured by increased alanine aminotransferase, inflammation, oxidative stress, and lipid accumulation was effectively prevented by fenofibrate. Fenofibrate significantly increased the expression of peroxisomal genes and proteins involved in peroxisomal biogenesis and function. HFD-induced attenuation of peroxisomal fatty acid oxidation was also significantly restored by fenofibrate, demonstrating the functional significance of peroxisomal fatty acid oxidation. In <i>Ppara</i> deficient mice, fenofibrate failed to maintain peroxisomal biogenesis and function in HFD-induced liver injury.Conclusion: The present data highlight the importance of PPARα-mediated peroxisomal fitness in the protective effect of fenofibrate against NAFLD.