Molecular remodeling of the renin-angiotensin system after kidney transplantation

Antlanger, Marlies; Domenig, Oliver; Kovarík, J; Kaltenecker, Christopher C.; Kopecky, Chantal; Poglitsch, Marko; Säemann, Marcus D.

doi:10.1177/1470320317705232

Cited by 13 publications

(9 citation statements)

References 44 publications

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“…The total variation (V) of each corresponding line scan was calculated according to the following formula: Briefly, angiotensin peptide levels and aldosterone were measured in conditioned lithium-heparin plasma at 37°C. Stable isotope-labeled internal standards for each metabolite were added to stabilized plasma samples at a concentration of 200 pg/mL and subjected to LC-MS/ MS-based angiotensin quantification by Attoquant Diagnostics, as previously described (3,7,16).…”

Section: Methodsmentioning

confidence: 99%

Progression of diabetic kidney disease in T2DN rats

Palygin

Spires

Levchenko

et al. 2019

American Journal of Physiology-Renal Physiology

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Diabetic kidney disease (DKD) is one of the leading pathological causes of decreased renal function and progression to end-stage kidney failure. To explore and characterize age-related changes in DKD and associated glomerular damage, we used a rat model of type 2 diabetic nephropathy (T2DN) at 12 wk and older than 48 wk. We compared their disease progression with control nondiabetic Wistar and diabetic Goto-Kakizaki (GK) rats. During the early stages of DKD, T2DN and GK animals revealed significant increases in blood glucose and kidney-to-body weight ratio. Both diabetic groups had significantly altered renin-angiotensin-aldosterone system function. Thereafter, during the later stages of disease progression, T2DN rats demonstrated a remarkable increase in renal damage compared with GK and Wistar rats, as indicated by renal hypertrophy, polyuria accompanied by a decrease in urine osmolarity, high cholesterol, a significant prevalence of medullary protein casts, and severe forms of glomerular injury. Urinary nephrin shedding indicated loss of the glomerular slit diaphragm, which also correlates with the dramatic elevation in albuminuria and loss of podocin staining in aged T2DN rats. Furthermore, we used scanning ion microscopy topographical analyses to detect and quantify the pathological remodeling in podocyte foot projections of isolated glomeruli from T2DN animals. In summary, T2DN rats developed renal and physiological abnormalities similar to clinical observations in human patients with DKD, including progressive glomerular damage and a significant decrease in renin-angiotensin-aldosterone system plasma levels, indicating these rats are an excellent model for studying the progression of renal damage in type 2 DKD.

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Section: Methodsmentioning

confidence: 99%

Progression of diabetic kidney disease in T2DN rats

Palygin

Spires

Levchenko

et al. 2019

American Journal of Physiology-Renal Physiology

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“…Briefly, angiotensin peptide levels were measured following 30 min of equilibration in conditioned lithium-heparin plasma at 37 °C and subsequent stabilization of equilibrium peptide levels. Stable isotope-labeled internal standards for each angiotensin metabolite (Ang I, Ang II, Ang-(1–7), Ang-(1–5), Ang-(2–8), Ang-(3–8)) as well as the deuterated internal standard for aldosterone (aldosterone D4) were added to stabilized plasma samples at a concentration of 200 pg/ml and subjected to liquid chromatography tandem-mass spectrometry (LC-MS/MS)-based angiotensin and steroid quantification by Attoquant Diagnostics as described previously 50 . As previously reported, using protease inhibitor-stabilized and equilibrated samples for angiotensin peptide quantification resulted in similar qualitative outcomes 51 .…”

Section: Methodsmentioning

confidence: 99%

Postprandial Effects on ENaC-Mediated Sodium Absorption

Blass

Klemens

Brands

et al. 2019

Sci Rep

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Recent studies have suggested that postprandial increases in insulin directly contribute to reduced urinary sodium excretion. An abundance of research supports the ability of insulin to augment epithelial sodium channel (ENaC) transport. This study hypothesized that ENaC contributes to the increase in renal sodium reabsorption following a meal. To test this, we used fasted or 4 hour postprandial Sprague Dawley rats to analyze ENaC expression and activity. We also assessed total expression of additional sodium transporters (Na+-Cl− cotransporter (NCC), Na+-K+-2Cl− cotransporter (NKCC2), and Na+-K+-ATPase (NKA)) and circulating hormones involved in the renin-angiotensin-aldosterone system (RAAS). We found that after carbohydrate stimulus, ENaC open probability increased in split-open isolated collecting duct tubules, while ENaC protein levels remained unchanged. This was supported by a lack of change in phosphorylated Nedd4-2, an E3 ubiquitin ligase protein which regulates the number of ENaCs at the plasma membrane. Additionally, we found no differences in total expression of NCC, NKCC2, or NKA in the postprandial rats. Lastly, there were no significant changes in RAAS signaling between the stimulated and fasted rats, suggesting that acute hyperinsulinemia increases ENaC activity independent of the RAAS signaling cascade. These results demonstrate that insulin regulation of ENaC is a potential mechanism to preserve sodium and volume loss following a meal, and that this regulation is distinct from classical ENaC regulation by RAAS.

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“…While the RAS after KTx is constantly affected by various hemodynamic and immunological factors, we have previously shown that the systemic RAS is restored early to physiological levels, i.e. within the first months after KTx indicating that it could present a potential target for pharmacological intervention 29 . However, during the past decade, the focus of interest on the RAS has shifted to the role of the local/tissue RAS in specific tissues 30–32 .…”

Section: Discussionmentioning

confidence: 98%

Intrarenal Renin-Angiotensin-System Dysregulation after Kidney Transplantation

Kovarík

Kaltenecker

Kopecky

et al. 2019

Sci Rep

Self Cite

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Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with chronic kidney disease (CKD). Yet, their clinical effects after kidney transplantation (KTx) remain ambiguous and local renin-angiotensin system (RAS) regulation including the ‘classical’ and ‘alternative’ RAS has not been studied so far. Here, we investigated both systemic and kidney allograft-specific intrarenal RAS using tandem mass-spectrometry in KTx recipients with or without established ACEi therapy (n = 48). Transplant patients were grouped into early (<2 years), intermediate (2–12 years) or late periods after KTx (>12 years). Patients on ACEi displayed lower angiotensin (Ang) II plasma levels ( P < 0.01) and higher levels of Ang I ( P < 0.05) and Ang-(1–7) ( P < 0.05) compared to those without ACEi independent of graft vintage. Substantial intrarenal Ang II synthesis was observed regardless of ACEi therapy. Further, we detected maximal allograft Ang II synthesis in the late transplant vintage group ( P < 0.005) likely as a consequence of increased allograft chymase activity ( P < 0.005). Finally, we could identify neprilysin (NEP) as the central enzyme of ‘alternative RAS’ metabolism in kidney allografts. In summary, a progressive increase of chymase-dependent Ang II synthesis reveals a transplant-specific distortion of RAS regulation after KTx with considerable pathogenic and therapeutic implications.

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Molecular remodeling of the renin-angiotensin system after kidney transplantation

Cited by 13 publications

References 44 publications

Progression of diabetic kidney disease in T2DN rats

Progression of diabetic kidney disease in T2DN rats

Postprandial Effects on ENaC-Mediated Sodium Absorption

Intrarenal Renin-Angiotensin-System Dysregulation after Kidney Transplantation

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