MO067DELETION AND BLOCKAGE OF KININ B1 RECEPTOR EXACERBATES CISPLATIN-INDUCED CKD

Abstract Background and Aims Kinins plays a major role in immune response, where kinin B2 receptor is constitutively expressed and kinin B1 receptor is induced under inflammatory stimuli. Kinin B1 receptor deletion and blockage has been shown to have beneficial effects in some models of renal diseases. Multiple acute renal insults, even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Our main objective was to determine the importance of kinin B1 receptor in tubulointerstitial fibrosis induced by ongoing cisplatin treatment. Method Male C57/Bl6 mice were divided in 3 groups, vehicle, cisplatin, cisplatin + R715 (kinin B1 receptor antagonist). Animals has been treated with multiple doses of cisplatin (7mg/kg i.p) once a week during 4 weeks and R715 (0.8mg/kg i.p) 48, 24 and 1 hour prior to cisplatin injections. We also used B1KO mice (C57Bl6 background) and WT mice (littermates). Mice were euthanized after 30 days of last cisplatin injection. Renal parameters, histology, real time PCR were performed to investigate renal injury, inflammation and fibrosis. Results Cisplatin treatment increases most of renal parameters, renal injury and fibrosis markers. Deletion of B1 receptor exacerbates significantly creatinine (WT CIS 0,60+0,03 B1KO 0,76+0,01 mg/dL), urea (WT CIS 111,8+5,638 B1KO CIS 240,8+28,60 mg/dL), and protein excretion (WT CIS 0,0058+0,0011 B1KO CIS 0,0121+0,0007 mg/24h). Association of cisplatin with R715 increased creatinine levels (veh 0,43+0,03 cis+R715 0,64+0,04 mg/dL), exacerbates urea (cis 95,51 + 3,926 cis+R715 158,9+14,40 mg/dL) and protein excretion (cis 0,012+0,002 cis+R715 0,018+0,003 mg/24h). Renal injury markers such as KIM-1 and TNF-a showed no significant differences. NGAL expression exacerbates (cis 2,53+0,44 cis+R715 5,66+1,34) and tubular injury score (cis 0,130+0,021 cis+R715 0,191+0,020) is higher in cisplatin+R715 group. Fibrosis markers a-SMA (cis 2,56+0,43 cis+R715 4,67+0,99), Col4 (cis 2,57+0,39 cis+R715 5,14+1,01) and Vimentin (2,69+0,31 cis+R715 4,62+0,98) were exacerbated in cisplatin treatment associated with R715. Picrosirius red staining were used to asses tubulointerstitial fibrosis, and we confirmed that R715 treatment here also exacerbates fibrosis (cis 0,225+0,025 cis+R715 0,345+0,042). Conclusion Here we show that both deletion and blockage of kinin B1 receptor has deleterious effects in renal injury and fibrosis induced by ongoing cisplatin treatment.

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P0123THE IMPORTANCE OF PPAR-ALPHA IN AKI TO CKD TRANSITION IN NEPHROPATHY INDUCED BY FOLIC ACID

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0123 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Gabriel Estrela ◽

Adriano Arruda ◽

Leandro Freitas-Lima ◽

Jonatan Barrera-Chimal ◽

Ronaldo Araujo

Keyword(s):

Folic Acid ◽

Chronic Phase ◽

Kidney Injury ◽

Tnf Alpha ◽

Renal Diseases ◽

Tubular Injury ◽

Ppar Alpha ◽

Beneficial Effects ◽

Stage Renal Disease ◽

End Stage

Abstract Background and Aims PPAR-alpha is a nuclear receptor which plays major role in the regulation of lipid metabolism, activation of PPAR-alpha has been shown to have beneficial effects in renal diseases. Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Our main objective was to determine the importance of PPAR-alpha in AKI to CKD transition in folic acid induced nephropathy. Method Male C57/Bl6 and PPARKO (C57Bl6 background) mice were divided in 4 groups, Control, Folic Acid, Gemfibrozil + Folic Acid and PPARKO + Folic Acid. Animals has been treated with single dose of Folic Acid (250mg/kg i.p) and Gemfibrozil (150mg/kg gavage) euthanized after 48 hours for AKI assessment and 28 days for CKD. Renal parameters, histology, real time PCR were performed to investigate renal injury, inflammation and fibrosis. Results After 48 hours of folic acid inducing AKI, PPARKO mice showed decreased urea levels (Folic Acid: 178,9±25,2 PPARKO: 92,4±15,5), less tubular injury (Folic Acid: 0,61±0,05 PPARKO: 0,21±0,03), lower mRNA expression of NGAL (Folic Acid; 32,2±7,67 PPARKO 3,74±1,71), KIM-1 (Folic Acid: 671,8±170,2 PPARKO: 43,4±29,7) and TNF-alpha (Folic Acid: 2,81±0,58 PPARKO: 0,67±0,14), while PPAR-alpha activation with gemfibrozil showed to have no effects in AKI. After 28 days of folic acid inducing CKD. PPARKO showed same levels of injury than folic acid alone treated mice, however PPAR-alpha activation with gemfibrozil decreased urea levels (Folic Acid: 79,2±3,2 Gemfibrozil: 46,1±3,8), showed less tubulointerstitial fibrosis (Folic Acid: 0,60±0,05 Gemfibrozil: 0,18±0,02) and lower urine protein/creatinine ratio (Folic Acid: 5,48±0,58 Gemfibrozil: 2,53±0,12), Conclusion PPAR-alpha deletion protects against AKI induced by folic acid but did not showed protection in chronic phase, in the other hand ppar-alpha activation with gemfibrozil did not protect in AKI but show to be effective in CKD.

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Renoprotective Effects of DPP-4 Inhibitors

Antioxidants ◽

10.3390/antiox10020246 ◽

2021 ◽

Vol 10 (2) ◽

pp. 246

Author(s):

Daiji Kawanami ◽

Yuichi Takashi ◽

Hiroyuki Takahashi ◽

Ryoko Motonaga ◽

Makito Tanabe

Keyword(s):

Diabetic Kidney Disease ◽

Experimental Studies ◽

Review Article ◽

Glucose Lowering ◽

Beneficial Effects ◽

Glucose Levels ◽

Membrane Bound ◽

Stage Renal Disease ◽

End Stage

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Dipeptidyl peptidase (DPP)-4 inhibitors are widely used in the treatment of patients with type 2 diabetes (T2D). DPP-4 inhibitors reduce glucose levels by inhibiting degradation of incretins. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. It has been shown that an increased renal DPP-4 activity is associated with the development of DKD. A series of clinical and experimental studies showed that DPP-4 inhibitors have beneficial effects on DKD, independent of their glucose-lowering abilities, which are mediated by anti-fibrotic, anti-inflammatory, and anti-oxidative stress properties. In this review article, we highlight the current understanding of the clinical efficacy and the mechanisms underlying renoprotection by DPP-4 inhibitors under diabetic conditions.

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Causes of Increased Renal Echogenicity in Pediatric Patients

PEDIATRICS ◽

10.1542/peds.72.6.840 ◽

1983 ◽

Vol 72 (6) ◽

pp. 840-846

Author(s):

Alan M. Krensky ◽

Joseph M. Reddish ◽

Rita Littlewood Teele

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

End Stage Renal Disease ◽

Pediatric Patients ◽

Renal Diseases ◽

Polycystic Kidney ◽

Renal Size ◽

Stage Renal Disease ◽

End Stage ◽

Echogenic Kidneys

Review of 2,700 abdominal ultrasonic examinations revealed 56 patients whose kidneys showed increased echogenicity. Echogenic kidneys were associated with medical renal disease in 94% of cases (30% glomerular, 48% tubulointerstitial, 16% end-stage) and with no detectable renal disease in 6% (three patients). Patterns of increased echogenicity and renal size were evaluated. Specific patterns occurred in end-stage renal disease and polycystic kidney disease. Other medical renal diseases had overlapping ultrasonographic features. Some generalizations could be made although increased echogenicity was often nonspecific.

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Renal medicine

10.1093/med/9780198810858.003.0008 ◽

2021 ◽

pp. 353-382

Author(s):

Gopesh K. Modi ◽

Vivekanand Jha

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

Rapidly Progressive Glomerulonephritis ◽

Kidney Injury ◽

Renal Stones ◽

Renal Diseases ◽

Acute Glomerulonephritis ◽

Glomerular Diseases ◽

Stage Renal Disease ◽

End Stage

Assessing renal function, Urinalysis, Proteinuria, Hematuria, Chyluria, Imaging in renal disease, Kidney biopsy, Acute Kidney Injury (AKI), Chronic Kidney Disease (CKD), Diabetic Nephropathy, End Stage Renal Disease and Dialysis, Kidney Transplantation, Glomerular diseases, Acute glomerulonephritis, Urinary schistosomiasis (bilharzia), Infections and Kidney Disease, Rapidly Progressive glomerulonephritis, Tubulointerstitial Disease, Urinary Tract Infection, Vesico-ureteric reflux, Renal Stones, Renal Disease in Pregnancy, Renal Artery Stenosis, Renal Mass, Inherited Renal Diseases

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The Key Role of Epithelial to Mesenchymal Transition (EMT) in Hypertensive Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20143567 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3567 ◽

Cited By ~ 3

Author(s):

Teresa Seccia ◽

Brasilina Caroccia ◽

Maria Piazza ◽

Gian Paolo Rossi

Keyword(s):

Kidney Disease ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Renal Diseases ◽

Hypertensive Nephropathy ◽

Mesenchymal Transition ◽

Afferent Arterioles ◽

Stage Renal Disease ◽

End Stage

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the ‘classic’ view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.

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An Overview of Renal Diseases in Children in Pokhara

Journal of Nepal Paediatric Society ◽

10.3126/jnps.v27i2.1414 ◽

1970 ◽

Vol 27 (2) ◽

pp. 75-78 ◽

Cited By ~ 2

Author(s):

T Malla ◽

KK Malla ◽

A Thapalial ◽

MS Sharma

Keyword(s):

Renal Failure ◽

Renal Disease ◽

End Stage Renal Disease ◽

Renal Stone ◽

Laboratory Evaluation ◽

Renal Diseases ◽

Adequate Treatment ◽

Stage Renal Disease ◽

End Stage

Objective: To determine the current pattern and prevalence of renal diseases in childhood in this region of Nepal. Material and Methods: A retrospective study of the renal diseases in children attending the Pediatric OPD and those hospitalised in Manipal Teaching Hospital, Pokhara was done over a period of 6 years (September 2000- September 2006). A detailed clinical and laboratory evaluation was performed at baseline. The children were managed according to disease diagnosed. These cases are under follow up and some have undergone surgical treatment. Results: 228 children (123 boys & 105girls) were diagnosed to have renal disease. Among them 39.5% had urinary tract infection (UTI), 30.7 % were suffering from acute glomerulonephritis (AGN), 17.5% were cases of nephrotic syndrome (NS) and 12 % had some other problems for example, 6.14% had genetic defects, 2.63% had renal Stone, 2.2% had pre-renal acute renal failure, unexplained recurrent hematuria in 1.3%. All the cases of UTI underwent through investigation and were treated accordingly. All cases of AGN are planned for follow up for 1½ yrs and among them 3 required biopsy till date. All cases of NS are under regular follow-ups and 2 have undergone biopsy. Renal stone was operated successfully. All cases of acute and chronic renal failures had required dialysis. Out of 5 (2.5%) chronic renal failures, 2 with end stage renal disease expired after repeated hemodialysis and three are still requiring dialysis. Among the obstructive uropathies, 43 % had renal stone, 36 % had posterior urethral valve and 21% VUR. Conclusion: It can be concluded that renal disease is not uncommon in children. It can be completely cured with proper and adequate treatment. Sometimes it has a bad prognosis when it reaches end stage renal disease. Early recognition, timely treatment and regular follow up are mandatory in management of children with renal diseases. Key words: Renal disease pattern, UTI, AGN, NS, Obstructive Uropathy, Renal failure doi:10.3126/jnps.v27i2.1414 J. Nepal Paediatr. Soc. Vol.27(2) p.75-78

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Experimental and clinical rationale for use of MMF in nontransplant progressive nephropathies

AJP Renal Physiology ◽

10.1152/ajprenal.00209.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. F1167-F1175 ◽

Cited By ~ 22

Author(s):

Roberto Zatz ◽

Irene Lourdes Noronha ◽

Clarice Kazue Fujihara

Keyword(s):

Mycophenolate Mofetil ◽

Clinical Practice ◽

Renal Disease ◽

Renal Injury ◽

End Stage Renal Disease ◽

Allograft Rejection ◽

Immune Mediated ◽

Stage Renal Disease ◽

End Stage ◽

Inflammatory Action

The incidence of progressive nephropathies and, consequently, the population suffering from end-stage renal disease have increased steadily in recent years, posing an ever-growing cost, in both human and financial terms, to society. There is mounting evidence that, in both immune-mediated and nonimmune-mediated chronic nephropathies, renal inflammatory events are key to the propagation and perpetuation of renal injury. Mycophenolate mofetil (MMF) is an antilymphocyte agent recently introduced in clinical practice for the prevention of allograft rejection. The present review discusses clinical and experimental evidence that the anti-inflammatory action of MMF can be advantageously used to arrest immune- and nonimmune-mediated progressive injury of native kidneys as well.

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Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Molecular and Cellular Biology ◽

10.1128/mcb.00565-16 ◽

2017 ◽

Vol 37 (12) ◽

Cited By ~ 15

Author(s):

Janet Y. Leung ◽

Harper L. Wilson ◽

Kristin J. Voltzke ◽

Lindsay A. Williams ◽

Hyo Jin Lee ◽

...

Keyword(s):

Chronic Kidney Disease ◽

End Stage Renal Disease ◽

Tubulointerstitial Fibrosis ◽

Renal Epithelium ◽

Molecular Events ◽

Phenotypic Manifestation ◽

Patients At Risk ◽

Secretory Phenotype ◽

Stage Renal Disease ◽

End Stage

ABSTRACT Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.

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