Lack of A1 Adenosine Receptors Augments Diabetic Hyperfiltration and Glomerular Injury

Faulhaber-Walter, Robert; Chen, Limeng; Oppermann, Mona; Kim, Soo Mi; Huang, Yuning; Hiramatsu, Noriyuki; Mizel, Diane; Kajiyama, Hiroshi; Zerfas, Patricia M.; Briggs, Josephine P.; Kopp, Jeffrey B.; Schnermann, Jürgen

doi:10.1681/asn.2007060721

Cited by 81 publications

(77 citation statements)

References 37 publications

(42 reference statements)

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“…23 Studies about the role of AR in the progression of DN in rats have attributed to the A 2A subtype, a possible protective role in preventing inflammation-associated renal injury, 24 while a controversial role has been attributed to A 1 subtype in mediating glomerular hyperfiltration. 25,26 We have determined that the nucleoside adenosine is a regulator of the VEGF production in glomeruli of rat in vitro. 27 Therefore, the correlation of adenosine levels and alterations of glomerular functions in the diabetic state, as well as the possible pharmacological intervention remain to be explored in vivo.…”

mentioning

confidence: 99%

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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Diabetic nephropathy ranks as the most devastating kidney disease worldwide. It characterizes in the early onset by glomerular hypertrophy, hyperfiltration and mesangial expansion. Experimental models show that overproduction of vascular endothelial growth factor (VEGF) is a pathogenic condition for podocytopathy; however the mechanisms that regulate this growth factor induction are not clearly identified. We determined that the adenosine A 2B receptor (A 2B AR) mediates VEGF overproduction in ex vivo glomeruli exposed to high glucose concentration, requiring PKCa and Erk1/2 activation. The glomerular content of A 2B AR was concomitantly increased with VEGF at early stages of renal disease in streptozotocin-induced diabetic rats. Further, in vivo administration of an antagonist of A 2B AR in diabetic rats blocked the glomerular overexpression of VEGF, mesangial cells activation and proteinuria. In addition, we also determined that the accumulation of extracellular adenosine occurs in glomeruli of diabetic rats. Correspondingly, raised urinary adenosine levels were found in diabetic rats. In conclusion, we evidenced that adenosine signaling at the onset of diabetic kidney disease is a pathogenic event that promotes VEGF induction.

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mentioning

confidence: 99%

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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“…This increased proximal sodium reabsorption leads to decreased sodium delivery to and transport in the cells of the macula densa, with consequent reduction in ATP breakdown and adenosine production. Adenosine is a strong vasoconstrictor, and its reduction causes vasodilation of the afferent arteriole and thus hyperfiltration (32) (Fig. 1).…”

Section: Sglt2 Inhibitors and Glomerular Hyperfiltrationmentioning

confidence: 99%

SGLT2 Inhibitors and the Diabetic Kidney

et al. 2016

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Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addition to their glycemic and blood pressure benefits, may provide nephroprotective effects.Diabetes is a worldwide growing public health problem with high risks of severe microvascular and macrovascular complications. Diabetic nephropathy (DN) is a major burden among the chronic complications of diabetes, given that it affects ;30% of patients with diabetes. Indeed, DN is the most common cause of end-stage renal disease in the U.S. (1) and worldwide. Known risk factors for DN include hyperglycemia, hypertension, dyslipidemia, smoking, and obesity as well as ethnic, familial, and genetic predispositions (2). Key clinical trials have demonstrated that early interventions, especially those aimed at primary prevention, are by far more effective and that it is only possible to slow progression once DN is established (2). Thus, large intervention trials on the impact of long-term intensified glucose control on chronic diabetes complications, both in type 1 and type 2 diabetes (2-6), have documented the critical role of glycemic control i...

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“…Calculating GFR by the above shown formula (and as described in here 20 ) allows to detect impairment of kidney function 15 or glomerular hyperfiltration 8,23 as found in mice with type 1 diabetes mellitus (Figure 2).…”

Section: Preparation Of Standardsmentioning

confidence: 99%

“…These protocols retain the sensitivity of radioactive inulin by using fluorescence detection and circumventing the disadvantages of working with a radioactive labeled marker. The FITC-inulin assay was modified by others 7,8 and us 22,23 to take advantage of the microvolume capability of the NanoDrop 3300 fluorospectrometer. This allows reducing the total sample volume needed to <100 μl blood per GFR measurement.…”

Section: Introductionmentioning

confidence: 99%

A High-throughput Method for Measurement of Glomerular Filtration Rate in Conscious Mice

Rieg

2013

JoVE

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The measurement of glomerular filtration rate (GFR) is the gold standard in kidney function assessment. Currently, investigators determine GFR by measuring the level of the endogenous biomarker creatinine or exogenously applied radioactive labeled inulin ( 3 H or 14 C). Creatinine has the substantial drawback that proximal tubular secretion accounts for ~50% of total renal creatinine excretion and therefore creatinine is not a reliable GFR marker. Depending on the experiment performed, inulin clearance can be determined by an intravenous single bolus injection or continuous infusion (intravenous or osmotic minipump). Both approaches require the collection of plasma or plasma and urine, respectively. Other drawbacks of radioactive labeled inulin include usage of isotopes, time consuming surgical preparation of the animals, and the requirement of a terminal experiment. Here we describe a method which uses a single bolus injection of fluorescein isothiocyanate-(FITC) labeled inulin and the measurement of its fluorescence in 1-2 μl of diluted plasma. By applying a two-compartment model, with 8 blood collections per mouse, it is possible to measure GFR in up to 24 mice per day using a special work-flow protocol. This method only requires brief isoflurane anesthesia with all the blood samples being collected in a non-restrained and awake mouse. Another advantage is that it is possible to follow mice over a period of several months and treatments (i.e. doing paired experiments with dietary changes or drug applications). We hope that this technique of measuring GFR is useful to other investigators studying mouse kidney function and will replace less accurate methods of estimating kidney function, such as plasma creatinine and blood urea nitrogen.

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Lack of A1 Adenosine Receptors Augments Diabetic Hyperfiltration and Glomerular Injury

Cited by 81 publications

References 37 publications

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

SGLT2 Inhibitors and the Diabetic Kidney

A High-throughput Method for Measurement of Glomerular Filtration Rate in Conscious Mice

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