scholarly journals Renal ROCK Activation and Its Pharmacological Inhibition in Patients With Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Keiichiro Matoba ◽  
Kensuke Sekiguchi ◽  
Yosuke Nagai ◽  
Yusuke Takeda ◽  
Hiroshi Takahashi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Body Height ◽  
Coiled Coil ◽  
Renal Outcome ◽  
Rock Inhibitor ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Patients With Diabetes ◽  
Rock Activity

Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase with essential roles in cytoskeletal functions. Substantial evidence implicates ROCK as a critical regulator in the inception and progression of diabetic nephropathy through a mechanism involving mesangial fibrosis, podocyte apoptosis, and endothelial inflammation. Despite these experimental observations, human data is lacking. Here we show that the phosphorylated form of myosin phosphatase targeting subunit 1 (MYPT1), a ROCK substrate, was increased in both the glomerular and tubulointerstitial areas in patients with histologically confirmed diabetic nephropathy. We also conducted a retrospective pilot analysis of data from patients with diabetes to assess the renoprotective effects of fasudil, an ATP-competitive ROCK inhibitor licensed in Japan for the prevention of vasospasm following subarachnoid hemorrhage. Fifteen subjects (male, n = 8; female, n = 7; age 65.7 ± 14.7 years; body height, 161.1 ± 12.6 cm; body weight, 57.6 ± 13.7 kg; body mass index, 22.4 ± 3.7 kg/m2) were enrolled to evaluate blood pressure and the renal outcome after fasudil treatment. Of note, proteinuria was significantly reduced at the end of the fasudil treatment without affecting the blood pressure or estimated glomerular filtration rate. Taken together, these findings suggest that the administration of fasudil could be associated with a better renal outcome by inhibiting the ROCK activity in patients with diabetes.

A visible light-controllable Rho kinase inhibitor based on a photochromic phenylazothiazole

2021 ◽  
Author(s):  
Kazuya Matsuo ◽  
Sampreeth Thayyil ◽  
Mitsuyasu Kawaguchi ◽  
Hidehiko Nakagawa ◽  
Nobuyuki Tamaoki
Keyword(s):  
Protein Kinase ◽  
Visible Light ◽  
Kinase Inhibitor ◽  
Coiled Coil ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Rho Kinase Inhibitor

Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine kinase, whose inhibitors are useful for the regulation of actomyosin system. Here, we developed a photoswitchable ROCK inhibitor based on a phenylazothiazole...

scholarly journals ASSESSMENT OF NEPHRIN AND PODOCIN LEVELS IN THE URINE OF PATIENTS WITH DIABETES MELLITUS

2017 ◽  
Vol 21 (2) ◽  
pp. 33-40
Author(s):  
I. N. Bobkova ◽  
A. A. Shchukina ◽  
M. V. Shestakova
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Serum Creatinine ◽  
Arterial Hypertension ◽  
Healthy Subjects ◽  
Early Diagnostics ◽  
Urinary Levels ◽  
Patients With Diabetes ◽  
Early Diabetic Nephropathy

THE AIM:to assess excretion value of podocytes injury biomarkers in urine and to clarify their significance for early diabetic nephropathy (DN) diagnostics in diabetes mellitus (DM) patients with different severity of albuminuria (AU)/proteinuria(PU).PATIENTS AND METHODS.74 DM pts were studied, including 30 with type1 DM (T1DM) and 44 pts with type2 DM (T2DM). They were divided into three groups: 41 pts with AU <30 mg/gCr (A1), 13 pts with AU 30-300 mg/gCr (A2), 20 pts with PU (A3). CKD S1 was revealed in 41pts, CKD S2 – in 25 pts, CKD S3 – in 8 pts. Arterial hypertension was observed in 52 pts of 74(70%), mainly in T2DM. 10 healthy subjects were studied as control. Urinary levels of nephrin and podocin (an important slit diaphragm proteins) were measured by ELISA.RESULTS.Nephrinuria (NU) >5,84ng/ml/g, which not detecting in controls, was revealed in 63% of A1 pts, in 77% – in A2, in 80% – in A3. Podocinuria (PdU)>1,73ng/ml/g was revealed in 78% of A1 pts, in 54% of A2 and in 83% – A3. NU in pts with PU was significantly higher than in AU<30 mg/g. PDU in groups with different AU/PU was equally high and has no differ between DM types. Direct correlation was obtained between NU and AU (R=0,947 p<0,05). NU and PdU in T1DM correlated directly with serum creatinine (R=0,489 p<0,05 and R=0,468 p<0,05) and indirectly with GFR (R=-0,461 p<0,05 and R=-0,36 р<0,05). In DM duration less than 5 years NU directly correlated with НbА1с level, in T2DM – indirectly with systolic blood pressure.CONCLUSON. Nephrin and podocin levels can be useful for early diagnostics and monitoring of DN. 

P5731Optimal blood pressure in diabetic hypertensive patients with overt proteinuria

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C J Lee ◽  
J Hwang ◽  
C Y Kang ◽  
H Kim ◽  
J Ha ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Lower Risk ◽  
Propensity Scores ◽  
Renal Outcome ◽  
Health Examination ◽  
Hypertensive Patients ◽  
Overt Proteinuria ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background Evidence for the benefit of intensive blood pressure lowering in diabetic nephropathy is not clear at this time. The objective of this study was to demonstrate whether lower mean blood pressure (BP) in treated hypertensive patients with diabetic nephropathy is associated with better prognosis. Methods From the National Health Insurance Service (NHIS) Health Examination Database, diabetic hypertensive subjects with proteinuria between 2009 and 2010 were selected and followed-up until 2015 (N=8,663). Mean of the recorded systolic and diastolic BP during follow-up health examinations were stratified into five categories (SBP: <120, 120 to <130, 130 to <140, 140 to <150, and ≥150 mmHg; DBP: <70, 70 to <80, 80 to <90, 90 to <100, and ≥100 mmHg). All-cause death, myocardial infarction (MI), stroke, and renal outcome (progression to end stage renal disease or doubling of serum creatinine) were examined by Cox proportional hazard models with the propensity scores adjusted method. Results Compared to SBP of 130 to <140 mmHg, SBP of 120 to <130 mmHg was associated with lower risk of all-cause death (HR=0.78; 95% CI, 0.64–0.95), stroke (HR: 0.65; 95% CI, 0.45–0.94), and renal outcome (HR: 0.81; 95% CI, 0.68–0.97). SBP of <120 mmHg was associated with benefit for renal outcomes (HR: 0.69; 95% CI 0.55–0.88) but not with elevated risk of other outcomes. Compared to DBP of 80 to <90 mmHg, DBP of 70 to <80 mmHg were associated with lower risk of all-cause death (HR: 0.75; 95% CI, 0.64–0.88) but with higher risk of MI (HR: 1.52; 95% CI, 1.05–2.21). DBP of <70 mmHg was associated with reduced risk of all-cause death (HR: 0.79; 95% CI, 0.64–0.98). Conclusion In diabetic hypertensive subjects with overt proteinuria, deterioration of renal function decreased with decreasing SBP and the lowest risk of all-cause death and stroke were observed in SBP <130 mmHg. Low DBP was associated with low risk of all-cause death but there was a J curve phenomenon for MI in DBP of 70 to <80 mmHg.

scholarly journals NIMA-related kinase 9–mediated phosphorylation of the microtubule-associated LC3B protein at Thr-50 suppresses selective autophagy of p62/sequestosome 1

2019 ◽  
Vol 295 (5) ◽  
pp. 1240-1260 ◽  
Author(s):  
Birendra Kumar Shrestha ◽  
Mads Skytte Rasmussen ◽  
Yakubu Princely Abudu ◽  
Jack-Ansgar Bruun ◽  
Kenneth Bowitz Larsen ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Brca1 Gene ◽  
Effector Proteins ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Selective Autophagy ◽  
Sequestosome 1 ◽  
Interaction Partners ◽  
Impaired Binding

Human ATG8 family proteins (ATG8s) are active in all steps of the macroautophagy pathway, and their lipidation is essential for autophagosome formation. Lipidated ATG8s anchored to the outer surface of the phagophore serve as scaffolds for binding of other core autophagy proteins and various effector proteins involved in trafficking or fusion events, whereas those at the inner surface are needed for assembly of selective autophagy substrates. Their scaffolding role depends on specific interactions between the LC3-interacting region (LIR) docking site (LDS) in ATG8s and LIR motifs in various interaction partners. LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro. A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). NEK9 knockdown or knockout enhanced degradation of the autophagy receptor and substrate p62. Of note, the suppression of p62 degradation was mediated by NEK9-mediated phosphorylation of LC3B Thr-50. Consistently, reconstitution of LC3B-KO cells with the phospho-mimicking T50E variant inhibited autophagic p62 degradation. PKCζ knockdown did not affect autophagic p62 degradation, whereas STK3/4 knockouts inhibited autophagic p62 degradation independently of LC3B Thr-50 phosphorylation. Our findings suggest that NEK9 suppresses LC3B-mediated autophagy of p62 by phosphorylating Thr-50 within the LDS of LC3B.

scholarly journals ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice

FEBS Letters ◽  
1996 ◽  
Vol 392 (2) ◽  
pp. 189-193 ◽  
Author(s):  
Osamu Nakagawa ◽  
Kazuko Fujisawa ◽  
Toshimasa Ishizaki ◽  
Yuji Saito ◽  
Kazuwa Nakao ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

scholarly journals Risk factors for the development of diabetic nephropathy

2009 ◽  
Vol 137 (1-2) ◽  
pp. 18-26 ◽  
Author(s):  
Miodrag Antic ◽  
Aleksandra Jotic ◽  
Milan Radovic ◽  
Jelena Seferovic ◽  
Nebojsa Lalic ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Kidney Function ◽  
Kidney Volume ◽  
Factors Associated ◽  
Patients With Diabetes ◽  
Dm Type 2

Introduction. Results of epidemiological analysis show that one third of patients with diabetes mellitus develop diabetic nephropathy (DN). Strategies used until now to slow down the progression of DN were initiated when the symptoms of DN were already present. Objective. Our objective was to analyze the prevalence and characteristics of DN and to determine the factors leading to DN. Methods. Fifty-two patients with diabetes mellitus (DM) - 32 with type 1 aged 32 years and 20 with type 2 aged 59 years - were referred from the Institute of Endocrinology, Diabetes and Metabolic Diseases to the Department of Nephrology for kidney function evaluation. Apart from routine laboratory analyses, glomerular filtration rate was calculated using the MDRD formula (modification of diet in renal disease), the size of the kidney was measured by ultrasound, and kidney volume was calculated using the ellipsoid formula. Results Thirty percent of the patients revealed normal (eight patients with DM type 1) or satisfactory kidney function (eight patients with DM type 1) with physiological proteinuria. Micro-albuminuria (MAU) or pathological proteinuria (PRT) were found in 10 and 9 patients, respectively, with DM type 1, while decreased kidney function was found in one patient without proteinuria. MAU or PRT were found in four and eight patients, respectively, with DM type 2 and decreased kidney function in four patients without proteinuria. Kidney function was significantly lower in patients with DM type 2 in comparison to DM type 1, while the patients with decreased kidney function had a higher PRT. Compared to DM type 2, in DM type 1 patients, the kidney was longer, and parenchymal artery resistance index was lower in DM type 1 patients compared to DM type 2. Factors associated with DN were patient's age, duration of diabetes, systolic blood pressure, HbA1c and kidney volume. Conclusion. The prevalence of DN among the studied patients was 70%. Treatable factors associated with the development of DN are strict control of blood pressure and glycaemia control.

MO479BLOOD PRESSURE CONTROL AND OUTCOMES IN DIABETIC RENAL DISEASE : EVIDENCE FROM A TUNISIAN COHORT

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Boukhtioua Mariem ◽  
Mami Ikram ◽  
Tlili Syrine ◽  
Ghabi Hiba ◽  
Hela Jbali ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Urinary Albumin Excretion ◽  
Pressure Control ◽  
Urinary Albumin ◽  
Patients With Diabetes ◽  
Group B ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims Diabetic nephropathy (DN) is associated with a high incidence of cardiovascular morbidity and mortality. The relationship between hypertension and diabetic nephropathy is complex and blood pressure (BP) control is an important management strategy in the prevention of its onset and progression .The aim of this study was to determine whether blood pressure control delays the progression of DN and prevents macrovascular complications in patients with diabetes mellitus. Method Hypertension guidelines advocate treating systolic blood pressure to less than 130 mm Hg and diastolic blood pressure to less than 80 mmHg for patients with diabetes mellitus and overt nephropathy.The relationship between blood pressure and progression of nephropathy was studied in 120 diabetic and hypertensive patients with established diabetic nephropathy. We divided hypertensive patients with stage 1 to 3 CKD already treated with antihypertensive therapy into 2 groups: those with BP &lt; 130/80 mmHg were designated as Group A (n=66) and those with BP&gt; 130/80 as Group B (n=54). Serum creatinine level as well as urinary albumin excretion were measured at 3 months,6 months, one year,2 years and at last visit during follow-up.The GFR was calculated using the Modification of diet in renal disease formula.The kidney disease outcome was defined as time to end-stage renal disease. The cardiovascular outcome was defined as time to myocardial infarction, stroke,ischemic stroke, hospitalization for heart failure, or revascularization. Results During the mean follow up period of 33,8 ± 11,7 months, the primary end point of end-stage renal disease occured in 9 patients (7 patients in Group B versus 2 patients in groupe A) while 11 hypertensive patient experienced a cardiovascular event.  The decline rate in GFR was significantly more important in groupe B (p&lt;0,05). However, little difference existed between the two groups in urinary albumin excretion. Blood pressure control was not associated with improved cardiovascular outcomes when comparing the two groups. Conclusion The results of our study indicate that an uncontrolled hypertension is associated with a rapid progression of kidney impairment in diabetic patients with overt nephropathy but no relationship with the incidence of cradiovascular events was seen in our population.

scholarly journals Sgk, a Putative Serine/Threonine Kinase, Is Differentially Expressed in the Kidney of Diabetic Mice and Humans

1999 ◽  
Vol 10 (12) ◽  
pp. 2488-2494
Author(s):  
JANET M. KUMAR ◽  
DAVID P. BROOKS ◽  
BARBARA A. OLSON ◽  
NICHOLAS J. LAPING
Keyword(s):  
Cell Culture ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Diabetic Mouse ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Serine Threonine Kinase ◽  
Differential Display Pcr ◽  
Threonine Kinase ◽  
Progression Of Renal Disease

Abstract. Differential display PCR was used to identify alternate expression of serum glucocorticoid-regulated kinase (Sgk) mRNA in diabetes-induced renal disease. Differential expression of Sgk mRNA was identified in the kidneys of normal and obese db/db mice, a model of select aspects of human diabetic nephropathy. Sgk mRNA was selectively increased in diabetic mouse kidneys. The Sgk mRNA levels remained constant in other tissues from obese db/db mice. An increase in Sgk mRNA was also observed in the human diabetic kidney. In addition, thrombin, which may play a role in the progression of renal disease, increased Sgk message in cell culture. Because the diabetes-induced increase in Sgk was only observed in the kidney, which is particularly susceptible to diabetes-induced damage, Sgk may play a role in diabetic nephropathy.

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