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Redox Biology Dec 2022Oxidative stress is an essential component in the progression of diabetic kidney disease (DKD), and the transcription factor NF-E2-related factor-2 (Nrf2) plays critical...
Oxidative stress is an essential component in the progression of diabetic kidney disease (DKD), and the transcription factor NF-E2-related factor-2 (Nrf2) plays critical roles in protecting the body against oxidative stress. To clarify the roles of Nrf2 in protecting against DKD, in this study we prepared compound mutant mice with diabetes and loss of antioxidative defense. Specifically, we prepared compound Ins2 (Akita) and Nrf2 knockout (Akita::Nrf2) or Akita and Nrf2 induction (Akita::Keap1) mutant mice. Eighteen-week-old Akita::Nrf2 mice showed more severe diabetic symptoms than Akita mice. In the Akita::Nrf2 mouse kidneys, the glomeruli showed distended capillary loops, suggesting enhanced mesangiolysis. Distal tubules showed dilation and an increase in 8-hydroxydeoxyguanosine-positive staining. In the Akita::Nrf2 mouse kidneys, the expression of glutathione (GSH) synthesis-related genes was decreased, and the actual GSH level was decreased in matrix-assisted laser desorption/ionization mass spectrometry imaging analysis. Akita::Nrf2 mice exhibited severe inflammation and enhancement of infiltrated macrophages in the kidney. To further examine the progression of DKD, we compared forty-week-old Akita mouse kidney compounds with Nrf2-knockout or Nrf2 mildly induced (Akita::Keap1) mice. Nrf2-knockout Akita (Akita::Nrf2) mice displayed severe medullary cast formation, but the formation was ameliorated in Akita::Keap1 mice. Moreover, in Akita::Keap1 mice, tubule injury and inflammation-related gene expression were significantly suppressed, which was evident in Akita::Nrf2 mouse kidneys. These results demonstrate that Nrf2 contributes to the protection of the kidneys against DKD by suppressing oxidative stress and inflammation.
Topics: Animals; Mice; Diabetic Nephropathies; Glutathione; Inflammation; Kelch-Like ECH-Associated Protein 1; Kidney; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Diabetes Mellitus, Experimental
PubMed: 36335764
DOI: 10.1016/j.redox.2022.102525 -
Clinical Kidney Journal Jul 2022Organ crosstalk allows the interaction between systems to adapt to a constant changing environment, maintaining homeostasis. The process of placentation and the new... (Review)
Review
Organ crosstalk allows the interaction between systems to adapt to a constant changing environment, maintaining homeostasis. The process of placentation and the new hormonal environment during pregnancy trigger physiological changes that modulate kidney function to control extracellular volume, acid-base balance and filtration of metabolic waste products. The bidirectional communication means that acute or chronic dysfunction of one organ can compromise the other. Abnormal placentation in pregnancy-related hypertensive disorders such as pre-eclampsia and HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome leads to the release of antiangiogenic factors that may cause kidney injury (thrombotic microangiopathy, glomeruloendotheliosis, mesangiolysis and vasoconstriction of peritubular vessels). These hypertensive disorders are a key cause of kidney injury in gestation, which increases maternal morbimortality and adverse foetal outcomes. Conversely, prior kidney injury or causes of kidney injury (diabetes, lupus, glomerulonephritis or other forms of chronic kidney disease) increase the risk of developing hypertensive pregnancy disorders, providing a baseline higher risk. Inherited kidney diseases are a special concern, given the potential for genetic predisposition to kidney disease in the foetus. Understanding the bidirectional potential for compromise from placenta to kidney and vice versa provides a better framework to limit damage to both organs and improve maternal and foetal outcomes.
PubMed: 35756742
DOI: 10.1093/ckj/sfac060 -
Journal of Diabetes Research 2020Diabetic nephropathy (DN) is the main factor leading to end-stage renal disease (ESRD) and subsequent morbidity and mortality. Importantly, the prevalence of DN is... (Review)
Review
Diabetic nephropathy (DN) is the main factor leading to end-stage renal disease (ESRD) and subsequent morbidity and mortality. Importantly, the prevalence of DN is continuously increasing in developed countries. Many rodent models of type 1 and type 2 diabetes have been established to elucidate the pathogenesis of diabetes and examine novel therapies against DN. These models are developed by chemical, surgical, genetic, drug, and diet/nutrition interventions or combination of two or more methods. The main characteristics of DN including a decrease in renal function, albuminuria and mesangiolysis, mesangial expansion, and nodular glomerulosclerosis should be exhibited by an animal model of DN. However, a rodent model possessing all of the abovementioned features of human DN has not yet been developed. Furthermore, mice of different genetic backgrounds and strains show different levels of susceptibility to DN with respect to albuminuria and development of glomerular and tubulointerstitial lesions. Therefore, the type of diabetes, development of nephropathy, duration of the study, cost of maintaining and breeding, and animals' mortality rate are important factors that might be affected by the type of DN model. In this review, we discuss the pros and cons of different rodent models of diabetes that are being used to study DN.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Humans; Kidney Failure, Chronic; Mice; Rats; Rodentia
PubMed: 32566684
DOI: 10.1155/2020/9416419 -
Kidney International Jul 1983
Review
Topics: Aneurysm; Animals; Capillaries; Diabetic Nephropathies; Disease Models, Animal; Glomerulonephritis; Humans; Hypertension, Renovascular; Ischemia; Kidney Diseases; Kidney Glomerulus; Microscopy, Electron; Rabbits; Rats; Snake Venoms; Thrombosis
PubMed: 6353041
DOI: 10.1038/ki.1983.119 -
World Journal of Diabetes Oct 2023Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations... (Review)
Review
Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure. The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments, such as the vascular system and glomeruli. Glomerular alterations include thickening of the glomerular basement membrane, loss of podocytes, and segmental mesangiolysis, which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules. Beyond lesions directly related to diabetes, awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, and other primary or secondary renal disorders. Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches. However, the relationship between diabetes and the kidney is bidirectional; thus, new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases. Here, we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course, differential diagnosis, and therapeutic oppor-tunities offered by novel drugs.
PubMed: 37970131
DOI: 10.4239/wjd.v14.i10.1450 -
Current Opinion in Nephrology and... May 2011Progress in identification of effective therapies for diabetic nephropathy continues to be limited by the lack of ideal animal models. Here we review the current status... (Review)
Review
PURPOSE OF REVIEW
Progress in identification of effective therapies for diabetic nephropathy continues to be limited by the lack of ideal animal models. Here we review the current status of some leading murine models of this disorder.
RECENT FINDINGS
A consensus statement of the Animals Models of Diabetic Complications Consortium sets forth guidelines and standards for measuring renal function and structural parameters necessary for validating murine models of diabetic nephropathy. Two murine models exploiting endothelial nitric oxide synthase (eNOS) deficiency as a major susceptibility factor for development of diabetic nephropathy are among the very few options for studying features of advanced diabetic nephropathy. Akita and OVE26 mice with mutations that result in Type I diabetes are also useful models of diabetic nephropathy. The recently described BTBR ob/ob (leptin deficient) mouse with Type II diabetes demonstrates key features of early podocyte loss and mesangiolysis characteristic of human diabetic nephropathy.
SUMMARY
While there are many murine models of mesangial matrix expansion in the setting of diabetes, few progress to develop advanced diabetic lesions. Mice with eNOS deficiency, OVE26 mice, and the recently described BTBR ob/ob mouse currently appear to be the best murine models of advanced disease. A model that allows testing of interventions that modulate podocyte loss and regeneration, such as the BTBR ob/ob mouse, may be of particular benefit in developing therapeutics for diabetic nephropathy.
Topics: Animals; Calmodulin; Diabetic Nephropathies; Disease Models, Animal; Glomerular Mesangium; Humans; Insulin Resistance; Leptin; Mice; Nitric Oxide Synthase Type III; Receptor, Insulin
PubMed: 21422926
DOI: 10.1097/MNH.0b013e3283451901 -
Kidney Research and Clinical Practice Jun 2018The development of the glomerular injury in diabetic nephropathy involves interactions between podocytes, endothelium, and the mesangium. Loss of podocytes is an early... (Review)
Review
The development of the glomerular injury in diabetic nephropathy involves interactions between podocytes, endothelium, and the mesangium. Loss of podocytes is an early and critical step in the development of diabetic nephropathy, and analysis of structural lesions within the mesangium such as mesangiolysis implicate the loss of podocytes as a key mediating event. The BTBR / mouse has proved a useful tool to demonstrate that restoration of podocyte density, once thought to be an absolute barrier to glomerular repair, can be achieved with replacement of the hormone leptin that is constitutively absent in these mice. Restoration of podocyte density is associated with reversal of the structural lesions of morphologically advanced diabetic glomerular injury in this model. This finding, in conjunction with the demonstration in human diabetic patients with morphologically advanced diabetic nephropathy and with long-standing functioning pancreatic transplants of ten years duration that their diabetic nephropathy can be reversed, suggests that restoration of podocyte number and density is an appropriate target for the development of new therapeutics for diabetic nephropathy.
PubMed: 29971205
DOI: 10.23876/j.krcp.2018.37.2.106 -
Nature Reviews. Nephrology Jan 2011The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30-40% of patients with diabetes mellitus develop overt nephropathy, which... (Review)
Review
The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30-40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin-angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.
Topics: Animals; Diabetic Angiopathies; Diabetic Nephropathies; Disease Models, Animal; Endothelium, Vascular; Humans; Mice
PubMed: 21045790
DOI: 10.1038/nrneph.2010.152 -
Journal of the American Society of... Sep 2022The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear...
The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for >30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications. One, which uses novel serial section electron microscopy, reveals a shorter capillary pathway between the basins of the afferent and efferent arterioles. Such a pathway, when patent, may short-circuit the multitude of capillaries in the glomerular tuft. Notably, this shorter capillary route is enclosed within the glomerular mesangium. The second study used anti-Thy1.1-induced mesangiolysis and intravital microscopy to unequivocally establish the long-suspected contractile function of mesangial cells, which have the ability to change the geometry and curvature of glomerular capillaries. These studies led me to hypothesize the existence of a glomerular perfusion rheostat, in which the shorter path periodically fluctuates between being more and less patent. This action reduces or increases blood flow through the entire glomerular capillary tuft. A corollary is that the GFR is a net product of balance between the states of capillary perfusion, and that deviations from the balanced state would increase or decrease GFR. Taken together, these studies may pave the way to a more profound understanding of glomerular microcirculation under basal conditions and in progression of glomerulopathies.
Topics: Microcirculation; Kidney Glomerulus; Glomerular Mesangium; Arterioles; Kidney Tubules
PubMed: 35853715
DOI: 10.1681/ASN.2022030354 -
Nephron 2023This study aimed to determine if immune or nonimmune and acute or chronic lesions associated with mesangiolysis (MGLS) occurred in biopsy-proven pathological chronic...
INTRODUCTION
This study aimed to determine if immune or nonimmune and acute or chronic lesions associated with mesangiolysis (MGLS) occurred in biopsy-proven pathological chronic active antibody-mediated rejection (P-CAABMR) in kidney transplant biopsies.
METHODS
We evaluated MGLS in 41 patients with biopsy findings of P-CAABMR from January 2016 to December 2019. Histological scoring was evaluated by Banff classification. Multivariate logistic regression analysis was performed using a forward selection method.
RESULTS
Fifteen of the 41 P-CAABMR biopsies (36.6%) cases showed MGLS. The estimated glomerular filtration rate (eGFR) was significantly lower in the MGLS-positive compared with the MGLS-negative group, and proteinuria was significantly higher in the MGLS-positive compared with the MGLS-negative group. In the clinical model, multivariate analysis was performed using covariates of eGFR and duration after transplantation significantly correlated with MGLS by simple analysis, in addition to type of calcineurin inhibitor use (tacrolimus or cyclosporine), donor-specific antibodies, diabetes, and hypertension grade defined by use of antihypertensive therapy or/and blood pressure level. Only hypertension grade was significantly correlated with MGLS. In the pathological model, multivariate analysis was performed using the presence of FSGS and the aah and cg scores significantly correlated with MGLS by simple analysis, in addition to g and ptc scores. The cg score was significantly correlated with hypertension grade, duration after transplantation, g, ah, and aah.
CONCLUSION
Lower graft function and higher proteinuria was observed in MGLS of P-CAABMR. The Banff cg score was independently related to MGLS in multivariate analysis. Sustained glomerulitis, calcineurin inhibitor nephrotoxicity, and hypertension may cause Banff cg lesions, leading to MGLS in P-CAABMR.
Topics: Humans; Kidney Transplantation; Calcineurin Inhibitors; Kidney Diseases; Antibodies; Hypertension; Biopsy; Proteinuria; Graft Rejection; Kidney
PubMed: 37321180
DOI: 10.1159/000531573