The role of distal tubule and collecting duct sodium reabsorption in sunitinib-induced hypertension

Witte, Jeannine; Lampe, Josephine; Koenen, Anna; Urbaneck, I; Steinbach, Antje; Rettig, Rainer; Grisk, Olaf

doi:10.1097/hjh.0000000000001650

Cited by 8 publications

(10 citation statements)

References 33 publications

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“…In the present study, we confirm that FE Na is reduced in rats with early sunitinib‐induced hypertension 11, 12. After l ‐NAME administration via the left renal artery, renal function parameters obtained separately from both kidneys, in particular glomerular filtration rate and diuresis, showed clear side differences, indicating that side‐specific NOS inhibition was achieved as intended.…”

Section: Discussionsupporting

confidence: 79%

“…In this and previous studies,11, 12 we administered sunitinib at a dose that is effective in tumor treatment in rats33 to facilitate extrapolation of experimental findings on mechanisms underlying sunitinib‐induced hypertension to humans. We focus on the early phase of developing sunitinib‐induced hypertension to investigate mechanisms that lead to the arterial pressure rise with minimum interference by factors that may be secondary to vascular and renal damage 11, 25.…”

Section: Discussionmentioning

confidence: 99%

“…Sunitinib‐induced hypertension is salt‐sensitive, characterized by increased renal fractional sodium reabsorption and mitigated by diuretics,12, 50 suggesting that altered renal sodium handling contributes to this form of arterial hypertension. In its developmental phase, NO‐dependent vascular tone regulation is not compromised but renal cortical sGC expression is reduced.…”

Section: Discussionmentioning

confidence: 99%

“…cGMP inhibits sodium reabsorption in several nephron segments39 and is a mediator of pressure natriuresis 51. Previously, we could exclude that sunitinib raises sodium reabsorption in the convoluted distal tubule and collecting duct 12. The sunitinib‐induced sGC downregulation may result in low renal tubular and interstitial cGMP abundances that enhance sodium absorption in more proximal nephron segments such as the thick ascending loop of Henle and the proximal tubule, thereby leading to hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…In normotensive rats, the antiangiogenic RTKI sunitinib induces arterial hypertension accompanied by increased renal vascular resistance (RVR) and decreased renal fractional sodium excretion (FE Na ) 11, 12. The sunitinib‐induced reduction in FE Na is not accompanied by reduced fractional lithium excretion, suggesting that proximal tubular sodium absorption is not enhanced 11.…”

Section: Introductionmentioning

confidence: 99%

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Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

Witte

Mühlbauer

Braun

et al. 2018

JAHA

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BackgroundThe tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib‐induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib‐treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib‐induced hypertension.Methods and ResultsArterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib‐treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib‐treated rats. Nitrate supplementation did not mitigate sunitinib‐induced hypertension. Endothelium‐dependent reductions in renal vascular resistance were similar in control and sunitinib‐treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib‐treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α1‐subunit protein abundance were less in sunitinib‐treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15‐20 mm Hg in sunitinib‐treated rats.ConclusionsRenal cortical sGC is downregulated in the presence of intact endothelium‐dependent renal vascular resistance regulation in developing sunitinib‐induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib‐induced hypertension.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

Witte

Mühlbauer

Braun

et al. 2018

JAHA

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Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies

Du,

Li,

et al. 2024

Arch Toxicol

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Ocular and systemic vascular endothelial growth factor ligand inhibitor use and nephrotoxicity: an update

Rangaswamy,

Nagaraju,

Bhojaraja

et al. 2024

Int Urol Nephrol

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Tumor growth is intricately linked to the process of angiogenesis, with a key role played by vascular endothelial growth factor (VEGF) and its associated signaling pathways. Notably, these pathways also play a pivotal “housekeeping” role in renal physiology. Over the past decade, the utilization of VEGF signaling inhibitors has seen a substantial rise in the treatment of diverse solid organ tumors, diabetic retinopathy, age-related macular degeneration, and various ocular diseases. However, this increased use of such agents has led to a higher frequency of encountering renal adverse effects in clinical practice. This review comprehensively addresses the incidence, pathophysiological mechanisms, and current evidence concerning renal adverse events associated with systemic and intravitreal antiangiogenic therapies targeting VEGF-A and its receptors (VEGFR) and their associated signaling pathways. Additionally, we briefly explore strategies for mitigating potential risks linked to the use of these agents and effectively managing various renal adverse events, including but not limited to hypertension, proteinuria, renal dysfunction, and electrolyte imbalances.

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The role of distal tubule and collecting duct sodium reabsorption in sunitinib-induced hypertension

Abstract: ENaC-dependent and thiazide-sensitive sodium-retaining mechanisms are not overactive in sunitinib-induced hypertension but ENaC blockers and in particular thiazides may be suitable for its treatment.

Cited by 8 publications

References 33 publications

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies

Ocular and systemic vascular endothelial growth factor ligand inhibitor use and nephrotoxicity: an update

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