The Role of Angiotensin II in Glomerular Volume Dynamics and Podocyte Calcium Handling

Ilatovskaya, Daria V.; Palygin, Oleg; Levchenko, Vladislav; Endres, Bradley T.; Staruschenko, Alexander

doi:10.1038/s41598-017-00406-2

Cited by 44 publications

(42 citation statements)

References 62 publications

(63 reference statements)

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“…According to our previous findings, 25 podocytic TRPC6 is the channel that mainly contributes to changes in [Ca 2+ ] i in normal and pathologic conditions. Here, we tested the expression level of TPRC6 in the kidney cortex in normal and diabetic conditions; as summarized in Figure 3E, DKD development resulted in a significant increase in TRPC6 expression in both STZ-treated wild-type SS and SS Nox42/2 strains.…”

Section: Diabetes-induced Calcium Mishandling Is Attenuated In Ss Noxmentioning

confidence: 81%

“…Isolation and basal podocyte intracellular calcium ([Ca 2+ ] i ) measurements in rats and mice were done as described previously. [25][26][27] Isolated decapsulated glomeruli were incubated with Fura-2TH, AM and Fluo-4, AM (5 mM; Thermo Fisher Scientific) for 40 minutes at room temperature. Calcium imaging was performed as previously described.…”

Section: Isolation Of Glomeruli and Calcium Measurementsmentioning

confidence: 99%

“…Calcium imaging was performed as previously described. 3,[25][26][27] A laser scanning confocal microscope system (Nikon A1-R, NIS…”

Section: Isolation Of Glomeruli and Calcium Measurementsmentioning

confidence: 99%

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A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease

Ilatovskaya

Blass

Palygin

et al. 2018

JASN

Self Cite

106

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Loss of glomerular podocytes is an indicator of diabetic kidney disease (DKD). The damage to these cells has been attributed in part to elevated intrarenal oxidative stress. The primary source of the renal reactive oxygen species, particularly HO, is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived HO contributes to podocyte damage in DKD elevation of podocyte calcium. We used Dahl salt-sensitive (SS) rats with a null mutation for the gene (SS) and mice with knockout of the nonselective calcium channel TRPC6 or double knockout of TRPC5 and TRPC6. We performed whole animal studies and used biosensor measurements, electron microscopy, electrophysiology, and live calcium imaging experiments to evaluate the contribution of this pathway to the physiology of the podocytes in freshly isolated glomeruli. Upon induction of type 1 diabetes with streptozotocin, SS rats exhibited significantly lower basal intracellular Ca levels in podocytes and less DKD-associated damage than SS rats did. Furthermore, the angiotensin II-elicited calcium flux was blunted in glomeruli isolated from diabetic SS rats compared with that in glomeruli from diabetic SS rats. HO stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from 6-knockout mice and, in a similar manner, in podocytes from5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from 6-knockout or5/6 double-knockout mice were protected from damage induced by HO to the same extent. These data reveal a novel signaling mechanism involving NOX4 and TRPC6 in podocytes that could be pharmacologically targeted to abate the development of DKD.

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Section: Diabetes-induced Calcium Mishandling Is Attenuated In Ss Noxmentioning

confidence: 81%

Section: Isolation Of Glomeruli and Calcium Measurementsmentioning

confidence: 99%

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A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease

Ilatovskaya

Blass

Palygin

et al. 2018

JASN

Self Cite

106

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“…Then the conditions were changed to 37˚C (without γ-IFN) to induce cell differentiation into mature podocytes and cells were cultured for 10-14 days. Differentiated podocytes were then divided into five groups: Normal glucose (NG) group (5.6 mmol/l), high glucose (HG) group (30 mmol/l), high mannitol group (NG + mannitol 25 mmol/l), the valsartan (VAL) group (HG + the AngII receptor blocker VAR, 10 -5 mmol/l), and HS group [HG + the TRP channel inhibitor (35), SAR7334, 1 µM) cultured in 37˚C for 48 h.…”

Section: Glomerular Morphological Characteristicsmentioning

confidence: 99%

Participation of the AngII/TRPC6/NFAT axis in the pathogenesis of podocyte injury in rats with type 2 diabetes

Zhou

et al. 2019

Mol Med Report

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The canonical transient receptor potential channel 6 ion channel is expressed in podocytes and is an important component of the glomerular slit diaphragm. Focal segmental glomerulosclerosis is closely associated with TRPC6 gene mutations, and TRPC6 mediates podocyte injury induced by high glucose. Angiotensin II (AngII) has been revealed to enhance TRPC6 currents in certain types of cells, including podocytes and ventricular myocytes. It has been reported that glucose regulated TRPC6 expression in an AngII-dependent manner in podocytes and that this pathway is critical in diabetic nephropathy. In the present study, the role of TRPC6 detected by western blotting and reverse transcription-quantitative polymerase chain reaction in AngII-mediated podocyte injury was evaluated in rats with type 2 diabetes induced by high-calorie diets and streptozotocin. The results demonstrated that urinary albumin excretion was elevated, and morphological changes, including glomerular basement membrane thickening and podocyte process effacement, were observed. There was increased expression of AngII and TRPC6 in diabetic rats. The angiotensin receptor blocker valsartan significantly reduced TRPC6 and nuclear factor of activated T-cells (NFAT) overexpression in diabetic rats. These results in vivo were confirmed by studies in vitro, which demonstrated that inhibition of TRPC6 ameliorated high glucose-induced podocyte injury by decreasing NFAT mRNA levels. Taken together, the present results suggested that the AngII/TRPC6/NFAT axis may be a crucial signaling pathway in podocytes that is necessary for maintaining the integrity of the glomerular filtration barrier. In addition, TRPC6 may represent a potential therapeutic target for diabetic nephropathy.

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“…In contrast, Throssell and colleagues 11 found significant low molecular weight proteinuria in acidotic rats, implying a tubular origin. Recent data reveal that the integrity of the glomerular filter is crucially determined by the concerted actions of the cellular components of the glomerulus [12][13][14] , especially podocytes 15 , which appear to tightly regulate glomerular permeability. Moreover, several in vitro and in vivo studies have indicated that both extra-cellular acidemia and bicarbonate therapy can exacerbate intra-cellular acidosis 6,16 , conceivably leading to cellular dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Buffer Therapy in Acute Metabolic Acidosis: Effects on Acid-Base Status and Glomerular Permeability

Schnapauff

Piros

Rippe

et al. 2019

Preprint

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Background: Correction of acute metabolic acidosis using sodium bicarbonate is effective, but has been hypothesized to exacerbate intra-cellular acidosis causing cellular dysfunction.The effects of acidemia and bicarbonate therapy on the cellular components of the glomerular filtration barrier, crucial for the integrity of the renal filter, are as yet unknown. Controversy persists regarding the most appropriate method to assess acid-base status: the "Stewart approach" or the "Siggaard-Andersen approach" using the standard base excess (SBE). Methods:Here we performed physiological studies in anesthetized Sprague-Dawley rats during severe metabolic acidosis (HCl iv 6 mmol kg −1 ) and following bicarbonate (2.5 mmol kg −1 ) administration. We assessed glomerular permeability using sieving coefficients of polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400. Acid-base status was evaluated using SBE, standard bicarbonate, total CO 2 , the Stewart-Fencl strong ion difference (ΔSID = Na -Cl -38) and a theoretical model of plasma and erythrocyte strong ion difference. Results:Our data show that neither acidosis nor its correction with NaHCO 3 altered glomerular permeability. We identified ΔSID as a strong estimator of plasma base excess (as assessed using the Van Slyke equation). In silico modeling indicates that changes in the strong ion difference in erythrocytes would explain their buffering effect by means of a shift of anions from the extracellular fluid. Conclusion:These data demonstrate a remarkable tolerance of the glomerular filter to severe acute acidosis and bicarbonate therapy. Our results also cast light on the buffer mechanism in erythrocytes and the ability of different acid-base parameters to evaluate the extent of an acidbase disorder.

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The Role of Angiotensin II in Glomerular Volume Dynamics and Podocyte Calcium Handling

Cited by 44 publications

References 62 publications

A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease

A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease

Participation of the AngII/TRPC6/NFAT axis in the pathogenesis of podocyte injury in rats with type 2 diabetes

Buffer Therapy in Acute Metabolic Acidosis: Effects on Acid-Base Status and Glomerular Permeability

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