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Journal of the Formosan Medical... Aug 2018Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the... (Review)
Review
Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the world. The most characteristic marker of DKD is albuminuria, which is associated with renal disease progression and cardiovascular events. Renal hemodynamics changes, oxidative stress, inflammation, hypoxia and overactive renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of DKD, and renal fibrosis plays the key role. Intensified multifactorial interventions, including RAAS blockades, blood pressure and glucose control, and quitting smoking, help to prevent DKD development and progression. In recent years, novel agents are applied for preventing DKD development and progression, including new types of glucose-lowering agents, pentoxifylline, vitamin D analog paricalcitol, pyridoxamine, ruboxistaurin, soludexide, Janus kinase inhibitors and nonsteroidal minerocorticoid receptor antagonists. In this review, recent large studies about DKD are also summarized.
Topics: Albuminuria; Biomarkers; Diabetic Nephropathies; Disease Progression; Humans; Kidney Failure, Chronic; Pentoxifylline; Renin-Angiotensin System
PubMed: 29486908
DOI: 10.1016/j.jfma.2018.02.007 -
Asian Journal of Andrology 2018Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers.... (Review)
Review
Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.
Topics: Antineoplastic Combined Chemotherapy Protocols; Calcifediol; Calcitriol; Clinical Trials as Topic; Ergocalciferols; Humans; Male; Prostatic Neoplasms; Signal Transduction; Vitamin D; Vitamin D Deficiency
PubMed: 29667615
DOI: 10.4103/aja.aja_14_18 -
Frontiers in Medicine 2022Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular... (Review)
Review
Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular basement membrane caused by mutations in type IV collagen genes which result in defective type IV collagen α3, α4, or α5 chains, respectively. Alport syndrome has three different patterns of inheritance: X-linked, autosomal and digenic. In a study of CKD of unknown etiology type IV collagen gene mutations accounted for the majority of the cases of hereditary glomerulopathies which suggests that AS is often underrecognized. The natural history and prognosis in patients with AS is variable and is determined by genetics and environmental factors. At present, no preventive or curative therapies exist for AS. Current treatment includes the use of renin-angiotensin-aldosterone system inhibitors which slow progression of kidney disease and prolong life expectancy. Ramipril was found in retrospective studies to delay the onset of ESKD and was recently demonstrated to be safe and effective in children and adolescents, supporting that early initiation of Renin Angiotensin Aldosterone System (RAAS) blockade is very important. Mineralocorticoid receptor blockers might be favorable for patients who develop "aldosterone breakthrough." While the DAPA-CKD trial suggests a beneficial effect of SGLT2 inhibitors in CKD of non-metabolic origin, only a handful of patients had Alport in this cohort, and therefore conclusions can't be extrapolated for the treatment of AS with SGLT2 inhibitors. Advances in our understanding on the pathogenesis of Alport syndrome has culminated in the development of innovative therapeutic approaches that are currently under investigation. We will provide a brief overview of novel therapeutic targets to prevent progression of kidney disease in AS. Our review will include bardoxolone methyl, an oral NRf2 activator; lademirsen, an anti-miRNA-21 molecule; sparsentan, dual endothelin type A receptor (ETAR) and angiotensin 1 receptor inhibitor; atrasentan, oral selective ETAR inhibitor; lipid-modifying agents, including cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) inducers, discoidin domain receptor 1 (DDR1) inhibitors and osteopontin blocking agents; the antimalarial drug hydroxychloroquine; the antiglycemic drug metformin and the active vitamin D analog paricalcitol. Future genomic therapeutic strategies such as chaperone therapy, genome editing and stem cell therapy will also be discussed.
PubMed: 35547199
DOI: 10.3389/fmed.2022.848389 -
Cell Death & Disease Jan 2020Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently...
Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.
Topics: Acute Kidney Injury; Aldehydes; Animals; Antineoplastic Agents; Cell Death; Cell Line; Cisplatin; Creatinine; Cyclohexylamines; Ergocalciferols; Ferroptosis; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Scanning Transmission; Mitochondria; Phenylenediamines; Piperazines; RNA, Small Interfering; Receptors, Calcitriol
PubMed: 31996668
DOI: 10.1038/s41419-020-2256-z -
Autophagy Apr 2022Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found...
Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found that vitamin D (VD) and VDR (vitamin D receptor) played a renoprotective role by inhibiting inflammation and fibrosis. However, whether VD-VDR regulates autophagy disorders in DN remains unclear. In this study, we established a streptozotocin (STZ)-induced diabetic model in knockout (-KO) mice and VDR specifically overexpressed in renal proximal tubular epithelial cells (-OE) mice. Our results showed that paricalcitol (an activated vitamin D analog) or -OE could alleviate STZ-induced ALB (albumin) excretion, renal tubule injury and inflammation, while these were worsened in -KO mice. Defective autophagy was observed in the kidneys of STZ mice, which was more pronounced in -KO mice and could be partially restored by paricalcitol or -OE. In high glucose-induced HK-2 cells, defective autophagy and decreased PRKAA1/AMPK phosphorylation was observed, which could be partially restored by paricalcitol in a VDR-dependent manner. AMPK inhibitor abolished paricalcitol-induced autophagy activation, and AMPK activator restored the defective autophagy in high glucose-induced HK-2 cells. Furthermore, paricalcitol-mediated AMPK activation was abrogated by CAMKK2/CaMKKβ inhibition, but not by knockout. Meanwhile, paricalcitol rescued the decreased Ca concentration induced by high glucose. In conclusion, VD-VDR can restore defective autophagy in the kidney of STZ-induced diabetic mice, which could be attributed to the activation of the Ca-CAMKK2-AMPK pathway in renal tubular epithelial cells. ACTB/β-actin: actin beta;AGE: advanced glycation end-products;AMPK: AMP-activated protein kinase;CAMKK2/CaMKKβ: calcium-calmodulin dependent protein kinase kinase 2;CQ: chloroquine;DN: diabetic nephropathy;HG: high levels of glucose;KO: knockout;LG: low levels of glucose;MAP1LC3/LC3: microtubule associated protein 1 light chain 3;NOD2: nucleotide binding oligomerization domain containing 2;OE: overexpression;PAS: periodic acid Schiff; Pari: paricalcitol;PTECs: proximal renal tubule epithelial cells;RT: room temperature;SQSTM1/p62: sequestosome 1;STK11/LKB1: serine/threonine kinase 11;STZ: streptozotocin;TEM: transmission electron microscopy;VD: vitamin D;VDR: vitamin D receptor;WT: wild-type.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial Cells; Female; Glucose; Humans; Inflammation; Male; Mice; Mice, Knockout; Receptors, Calcitriol; Streptozocin; Vitamin D; Vitamins
PubMed: 34432556
DOI: 10.1080/15548627.2021.1962681 -
Medicina (Kaunas, Lithuania) Feb 2021Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the... (Review)
Review
Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin-Angiotensin-Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin-megalin-amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN.
Topics: Glomerulonephritis; Humans; Podocytes; Receptors, Calcitriol; Vascular Endothelial Growth Factor A; Vitamin D
PubMed: 33671780
DOI: 10.3390/medicina57020186 -
Journal of Advanced Research May 2022Although the synthetic vitamin D analogue, Paricalcitol, and omega-3 Fatty acids (ω-3) alleviated diabetic nephropathy (DN), their combination was not previously...
INTRODUCTION
Although the synthetic vitamin D analogue, Paricalcitol, and omega-3 Fatty acids (ω-3) alleviated diabetic nephropathy (DN), their combination was not previously explored.
OBJECTIVES
This study measured the potential ameliorative effects of single and dual therapies of Paricalcitol and/or ω-3 against DN.
METHODS
Forty rats were assigned as follow: negative (NC) and positive (PC) controls, Paricalcitol, ω-3 and Paricalcitol + ω-3 groups. Diabetes was generated by high-fat/high-fructose diet and a single streptozotocin injection (40 mg/kg). DN was confirmed by raised fasting blood glucose (FBG), polyuria, proteinuria, and decreased urine creatinine levels. Paricalcitol intraperitoneal injections (0.25 µg/Kg/day; 5 times/week) and oral ω-3 (415 mg/kg/day; 5 times/week) started at week-9 and for eight weeks.
RESULTS
The PC group showed hyperglycaemia, dyslipidaemia, abnormal renal biochemical parameters, elevated caspase-3 expression, and increased apoptosis by TUNEL technique. The mRNAs and proteins of the pathogenic molecules (TGF-β1/iNOS) and markers of tissue damage (NGAL/KIM-1) augmented substantially in the PC renal tissues relative to the NC group. The oxidative stress (MDA/HO/protein carbonyl groups) and pro-inflammatory (IL1β/IL6/TNF-α) markers increased, whereas the anti-inflammatory (IL10) and anti-oxidative (GSH/GPx1/GR/SOD1/CAT) declined, in the PC renal tissues. The monotherapy groups were associated with ameliorated FBG, lipid profile and renal functions, and diminished TGF-β1/iNOS/NGAL/KIM-1/Caspase-3 alongside the apoptotic index than the PC group. The oxidative stress and pro-inflammatory markers decreased, whilst the anti-oxidative and anti-inflammatory molecules escalated, in the monotherapy groups than the PC group. Although the Paricalcitol renoprotective actions were better than ω-3, all the biomarkers were abnormal than the NC group. Alternatively, the Paricalcitol + ω-3 protocol exhibited the best improvements in metabolic control, renal functions, oxidative stress, inflammation, and apoptosis. However, FBG and tissue damage were persistently higher in the co-therapy group than controls.
CONCLUSIONS
Both monotherapies showed modest efficacy against DN, whereas their combination displayed boosted renoprotection, possibly by enhancing renal anti-oxidant and anti-inflammatory pathways.
Topics: Animals; Anti-Inflammatory Agents; Caspase 3; Diabetes Mellitus; Diabetic Nephropathies; Ergocalciferols; Fatty Acids, Omega-3; Female; Humans; Hydrogen Peroxide; Lipocalin-2; Male; Rats; Transforming Growth Factor beta1
PubMed: 35572411
DOI: 10.1016/j.jare.2021.08.010 -
Theranostics 2023Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating...
Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Renal tubule specific ELA knockout ( KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
Topics: Mice; Animals; Microcirculation; Dinoprostone; Kidney; Acute Kidney Injury; Renal Insufficiency, Chronic; Reperfusion Injury; Ischemia; Peptide Hormones; Reperfusion
PubMed: 37351176
DOI: 10.7150/thno.84308 -
Biomedicines Dec 2022Chronic kidney disease-mineral and bone disorder is one of the complications associated with chronic kidney disease. About 10-50% of patients following kidney... (Review)
Review
Chronic kidney disease-mineral and bone disorder is one of the complications associated with chronic kidney disease. About 10-50% of patients following kidney transplantation have persistent hyperparathyroidism. Hypercalcaemic hyperparathyroidism has a negative impact on the kidney transplant outcome; therefore, it requires treatment. The data regarding the treatment of persistent hyperparathyroidism provided in scientific publications are divergent and contradictory. Therefore, the aim of our systematic review was to evaluate the efficacy of persistent hyperparathyroidism treatment in patients following kidney transplantation. The Cochrane, PubMed, and Scopus databases were browsed independently by two authors. The search strategy included controlled vocabulary and keywords. The effectiveness of calcitriol, paricalcitol, cinacalcet, and parathyroidectomy was compared and analysed. The mean calcium and parathormone (PTH) concentrations per patient in the group of paricalcitol increased by 1.27% and decreased by 35.14% (n = 248); in the group of cinacalcet decreased by 12.09% and 32.16% (n = 368); and in the group of parathyroidectomy decreased by 19.06% and 86.49% (n = 15) at the end of the study compared to the baseline (n = 244, n = 342 and n = 15), respectively. Paricalcitol, cinacalcet, and parathyroidectomy decreased the intact PTH level. Cinacalcet and parathyroidectomy lowered calcium levels in renal transplant patients with hypercalcaemia. Conversely, paricalcitol increased the serum calcium concentration. Cinacalcet seems to be a good candidate in the treatment of post-transplant hyperparathyroidism.
PubMed: 36672533
DOI: 10.3390/biomedicines11010025 -
Cell Death Discovery May 2023Activating transcription factor 4 (ATF4) is one of the key effectors of endoplasmic reticulum stress (ERS), ATF4/CHOP pathway-mediated ERS plays an important role in the...
Activating transcription factor 4 (ATF4) is one of the key effectors of endoplasmic reticulum stress (ERS), ATF4/CHOP pathway-mediated ERS plays an important role in the progression of acute kidney disease (AKI). We have previously reported that Vitamin D receptor (VDR) exert renoprotection in rodent AKI models. However, whether ATF4, as well as ERS, is involved in the protective effect of VDR in ischemia-reperfusion (I/R) induced AKI is unknown. Herein, we showed that VDR agonist paricalcitol and VDR overexpression alleviated I/R-induced renal injury and cells apoptosis with decreased ATF4 and attenuated ERS, while VDR deletion significantly resulted in further increased ATF4, more drastic ERS and renal injury in I/R mice models. In addition, paricalcitol remarkably reduced Tunicamycin (TM) induced ATF4 and ERS with attenuated renal injury, while VDR deletion aggravated the above changes in TM mice models. Moreover, overexpression of ATF4 partially abolished the effect of paricalcitol against TM-induced ERS and apoptosis, while inhibition of ATF4 enhanced the protective effect of paricalcitol. Bioinformatics analysis indicated potential VDR binding sites on ATF4 promotor sequence which were further confirmed by ChIP-qPCR and dual-luciferase reporter gene assay. In conclusion, VDR attenuated I/R-induced AKI by suppressing ERS partly via transcriptional regulation of ATF4.
PubMed: 37173347
DOI: 10.1038/s41420-023-01456-4