Kidneys Susceptible to Hypoxia: Mechanisms and Therapeutic Implications

Dogroulle B. Hans and Mark L. Hans^*
*Correspondence: Mark L. Hans, Department of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington, USA, Email:

Keywords

Hypoxia-induced damage • Renal pathophysiology • Hypoxia-Inducible Factors (HIFs)

Introduction

The kidneys are vital organs responsible for maintaining the body's internal environment, fluid balance, and waste elimination. As a result of their continuous filtration, reabsorption, and excretion processes, the kidneys require a substantial amount of oxygen to meet their high metabolic demands. However, the intricate architecture of the renal vasculature and the sensitive balance between oxygen supply and demand render the kidneys particularly susceptible to the detrimental effects of hypoxia, a state characterized by reduced oxygen availability.

Hypoxia in the kidneys can arise from various factors, including reduced blood flow due to circulatory disturbances, systemic hypoxemia, or impaired oxygen utilization at the cellular level. Regardless of the underlying cause, the consequences of kidney hypoxia can be far-reaching, as it disrupts essential physiological functions and may lead to acute or chronic kidney injury.

The cellular response to hypoxia is intricately governed by hypoxiainducible factors (HIFs), a family of transcription factors that orchestrate adaptive mechanisms to counteract oxygen deprivation. Under normoxic conditions, HIFs are rapidly degraded, but in hypoxia, they stabilize and translocate to the nucleus, where they activate the expression of numerous genes involved in angiogenesis, erythropoiesis, glucose metabolism, and cell survival. While HIF activation is crucial for the short-term adaptive response to hypoxia, sustained or excessive HIF activity can contribute to pathological processes, such as inflammation, fibrosis, and impaired tissue repair [1]. Renal hypoxia has emerged as a common underlying factor in various kidney diseases, including acute kidney injury, chronic kidney disease, diabetic nephropathy, and ischemic nephropathy. In these conditions, the delicate balance between oxygen supply and demand becomes disrupted, leading to cellular dysfunction, injury, and eventual organ damage. Understanding the complex interplay of molecular pathways involved in kidney susceptibility to hypoxia is essential for developing targeted therapeutic strategies to combat renal diseases effectively.

Literature Review

Hypoxia, a state of reduced oxygen supply, plays a pivotal role in the pathogenesis of various kidney diseases. The kidneys, being highly metabolic organs, are particularly susceptible to hypoxia-induced injury, leading to cellular dysfunction and impaired renal function. This review aims to explore the current literature on hypoxia-related kidney diseases, with a focus on the underlying mechanisms and therapeutic strategies employed to mitigate their adverse effects.

Hypoxia-related kidney diseases

Acute Kidney Injury (AKI): AKI is a prevalent condition characterized by a rapid decline in kidney function. Reduced renal blood flow, as seen in cases of sepsis or hypovolemia, leads to hypoxic conditions in the kidneys, triggering cellular damage and inflammation. Studies have demonstrated the central role of hypoxia-inducible factors in the adaptive response to AKI, making them potential targets for therapeutic interventions.

Chronic Kidney Disease (CKD): CKD is a progressive condition marked by the gradual loss of kidney function. Hypoxia plays a crucial role in CKD progression, with hypoxic microenvironments promoting fibrosis, inflammation, and cellular damage. The impaired vascular autoregulation and endothelial dysfunction in CKD exacerbate renal hypoxia, leading to tubulointerstitial injury. Novel therapies aimed at enhancing oxygen delivery and improving tissue oxygenation are currently being investigated.

Diabetic nephropathy: Diabetes is a significant risk factor for kidney disease, and diabetic nephropathy is one of its most common complications. Prolonged hyperglycemia and altered renal hemodynamics contribute to microvascular changes and local hypoxic zones in the kidneys. Therapeutic strategies targeting hypoxia, such as HIF stabilization or antioxidant therapies, have shown promising results in preclinical studies [2].

Ischemic nephropathy: Ischemic nephropathy results from reduced blood flow to the kidneys, leading to regional hypoxic zones and tissue damage. Revascularization approaches, including angiogenic therapies or endothelial progenitor cell-based interventions, have been explored to improve blood flow and oxygenation.

Therapeutic approaches

HIF stabilization: Strategies to stabilize HIFs under hypoxic conditions have gained considerable attention. Small molecule inhibitors of prolyl hydroxylases can prevent HIF degradation, enhancing its transcriptional activity. However, caution is required to avoid excessive HIF activation, which may lead to adverse effects.

Antioxidant therapies: Antioxidants have been investigated for their potential to counteract oxidative stress and ROS production induced by hypoxia. Preclinical studies have shown beneficial effects of antioxidant treatments in mitigating cellular damage.

Oxygen therapies: Supplemental oxygen administration or agents that enhance oxygen-carrying capacity, such as erythropoietin, have been explored to improve tissue oxygenation in hypoxia-related kidney diseases. However, the clinical efficacy and safety of such approaches require further investigation.

Promoting angiogenesis: Therapies aimed at promoting angiogenesis have shown promise in preclinical models of kidney hypoxia. Agents targeting angiogenic growth factors may enhance the formation of new blood vessels, improving oxygen delivery to hypoxic renal regions.

Preventive measures: Managing underlying conditions, such as diabetes and hypertension, can reduce the risk of hypoxia-related kidney diseases. Lifestyle modifications, including a healthy diet and exercise, may also contribute to preserving renal health.

Hypoxia is a common factor in the pathogenesis of various kidney diseases, including AKI, CKD, diabetic nephropathy, and ischemic nephropathy [3]. The therapeutic approaches discussed in this review highlight the potential of targeting hypoxia-related pathways to ameliorate kidney injury and improve renal outcomes. Continued research into the molecular mechanisms of kidney hypoxia and the translation of these findings into clinical trials are essential for developing effective therapies to combat hypoxia-related kidney diseases and enhance patient care.

Discussion

Physiology of kidney oxygenation

The physiology of kidney oxygenation is a finely tuned process essential for maintaining optimal renal function. The kidneys receive approximately 20-25% of cardiac output, emphasizing their high metabolic demands. Renal oxygenation primarily depends on the complex interplay of the renal vasculature, oxygen supply, and tissue oxygen consumption.

The renal arteries supply oxygenated blood to the kidneys, which then branches into smaller vessels, ultimately reaching the glomerular capillaries. The glomerular filtration process occurs in these capillaries, where blood is filtered to form the primary urine. Oxygen tension gradually decreases along the renal vascular tree due to oxygen consumption in the highly metabolic nephrons. An essential feature of renal physiology is autoregulation, which maintains a stable glomerular filtration rate and ensures consistent oxygen delivery to the nephrons. The myogenic response of the afferent arterioles and the tubuloglomerular feedback mechanism allow the kidneys to adjust their vascular resistance and perfusion pressure, thus counteracting fluctuations in systemic blood pressure and ensuring stable oxygen supply [4,5].

Overall, the complex architecture of the renal vasculature and the finely regulated autoregulation mechanism play pivotal roles in maintaining the delicate balance between oxygen supply and demand in the kidneys, ensuring optimal renal oxygenation for proper kidney function. Any disruption in this balance, such as in cases of hypoxia or impaired vascular regulation, can lead to kidney injury and contribute to the pathophysiology of various kidney diseases.

Hypoxia-Inducible Factors (HIFs) in renal hypoxia

Hypoxia-inducible factors are critical transcription factors that play a central role in the adaptive response to renal hypoxia. HIFs are heterodimeric proteins composed of an oxygen-sensitive alpha subunit (HIF-α) and a constitutively expressed beta subunit (HIF-β). Under normoxic conditions, Prolyl Hydroxylases (PHDs) hydroxylate specific proline residues on HIF-α, marking it for ubiquitin-mediated degradation via the Von Hippel-Lindau (VHL) complex. In response to reduced oxygen levels, the hydroxylation reaction is inhibited, preventing HIF-α degradation. Stabilized HIF-α subunits translocate to the nucleus, where they dimerize with HIF-β and bind to Hypoxia-Responsive Elements (HREs) in the promoter regions of target genes. This activates the transcription of numerous genes involved in cellular adaptation to hypoxia, such as Vascular Endothelial Growth Factor (VEGF), Erythropoietin (EPO), Glucose Transporters (GLUTs), and enzymes regulating glycolysis [6].

In the context of renal hypoxia, HIFs play a crucial role in enhancing oxygen delivery and cellular survival. Upregulation of VEGF promotes angiogenesis, increasing the density of peritubular capillaries to improve oxygen supply. EPO induction stimulates erythropoiesis, increasing red blood cell production to enhance oxygen-carrying capacity. Additionally, the upregulation of glycolytic enzymes and GLUTs allows cells to utilize glucose more efficiently under low oxygen conditions. While HIF activation is essential for the short-term adaptive response to renal hypoxia, sustained HIF activation can contribute to kidney injury and disease progression. Thus, understanding the precise regulation of HIFs in renal hypoxia is crucial for developing targeted therapeutic interventions to mitigate the adverse effects of hypoxia-related kidney diseases.

Cellular responses to hypoxia in the kidneys

In response to hypoxia in the kidneys, various cellular pathways are activated, leading to adaptive and maladaptive responses. One of the primary consequences is the upregulation of Hypoxia-Inducible Factors (HIFs), which initiate the transcription of genes involved in angiogenesis, erythropoiesis, glucose metabolism, and cell survival. This promotes the formation of new blood vessels, enhances oxygen-carrying capacity, and optimizes cellular energy utilization. However, prolonged or severe hypoxia can trigger maladaptive responses, including the activation of apoptosis, inflammation, and fibrosis pathways. The impairment of oxygen-dependent mitochondrial functions can lead to the production of reactive oxygen species, causing oxidative stress and cellular damage [7].

Renal cells, particularly proximal tubular cells, are highly sensitive to hypoxia-induced injury due to their intense metabolic activity and reliance on aerobic respiration. The cumulative effects of cellular responses to hypoxia contribute to kidney dysfunction, which is implicated in the pathogenesis of various kidney diseases, such as acute kidney injury and chronic kidney disease. Understanding these cellular responses is vital for developing targeted therapeutic strategies to protect against kidney injury and improve renal outcomes.

Mechanisms contributing to kidney susceptibility to hypoxia

Kidney susceptibility to hypoxia can be attributed to several interconnected mechanisms. The unique vascular architecture of the kidneys, characterized by a high-energy-consuming filtration process and an extensive peritubular capillary network, makes them particularly vulnerable to fluctuations in oxygen supply.

The proximal tubules, responsible for reabsorption and metabolic activities, are highly sensitive to hypoxia due to their reliance on aerobic respiration and limited capacity for anaerobic metabolism. The delicate balance between oxygen demand and supply in these cells can be easily disrupted, leading to cellular dysfunction and injury. Renal diseases, such as diabetic nephropathy and chronic kidney disease, often exhibit altered microcirculation and vascular endothelial dysfunction, exacerbating renal hypoxia. Impaired nitric oxide signaling and increased production of vasoconstrictors can further compromise blood flow regulation and exacerbate hypoxic conditions.

Mitochondrial dysfunction and oxidative stress also contribute to kidney susceptibility to hypoxia, as impaired mitochondrial respiration leads to increased ROS production, further damaging renal cells. Collectively, these mechanisms converge to increase the risk of hypoxic injury in the kidneys, making them highly susceptible to the adverse effects of reduced oxygen supply.

Hypoxia-related kidney diseases

Hypoxia is a common underlying factor in various kidney diseases. Several renal conditions are closely associated with reduced oxygen supply, leading to cellular injury and dysfunction. Some of the major hypoxia-related kidney diseases include:

Acute Kidney Injury (AKI): AKI is characterized by a sudden and significant decline in kidney function. It can result from reduced renal blood flow, such as in cases of hypovolemia or sepsis, leading to inadequate oxygen delivery to the kidneys. The hypoxia-induced cellular damage and inflammation contribute to the impairment of renal function.

Chronic Kidney Disease (CKD): CKD is a progressive condition characterized by a gradual loss of kidney function over time. Hypoxia plays a pivotal role in the pathogenesis of CKD. Vascular changes, glomerular injury, and tubulointerstitial fibrosis in CKD can lead to local hypoxic conditions, promoting renal tissue damage and impairing kidney function.

Diabetic nephropathy: Diabetes is a major risk factor for kidney disease. In diabetic nephropathy, prolonged hyperglycemia and altered renal hemodynamics lead to microvascular changes, contributing to renal hypoxia. Hypoxia-related injury in the kidneys accelerates disease progression and worsens kidney function in diabetic patients.

Ischemic nephropathy: Ischemic nephropathy results from reduced blood flow to the kidneys, often caused by renal artery stenosis. This condition leads to regional hypoxic zones in the kidney, ultimately contributing to tissue damage and progressive renal dysfunction.

Understanding the role of hypoxia in these kidney diseases is crucial for developing targeted therapies aimed at improving oxygen supply, mitigating cellular damage, and preserving renal function.

Therapeutic strategies for kidney hypoxia

Therapeutic strategies for kidney hypoxia focus on mitigating cellular damage, improving oxygen supply, and promoting tissue repair. Targeting hypoxia-inducible factors to enhance their activity may promote angiogenesis and erythropoiesis, improving oxygen delivery and utilization. However, careful regulation is essential to prevent excessive HIF activation, which could lead to detrimental effects. Antioxidants can counteract oxidative stress, reducing reactive oxygen species production and cellular damage caused by hypoxia. Supplemental oxygen administration or using agents that enhance oxygencarrying capacity (e.g., erythropoietin) can improve tissue oxygenation. Inducing the formation of new blood vessels (angiogenesis) can increase oxygen supply to hypoxic areas. Managing underlying conditions (e.g., diabetes, hypertension) and implementing lifestyle changes (e.g., healthy diet, exercise) can reduce the risk of kidney hypoxia-related diseases. Developing drugs targeting specific cellular pathways involved in hypoxia-induced injury may hold promise in protecting renal cells from hypoxic damage.

Conclusion

Kidney susceptibility to hypoxia represents a significant challenge in renal medicine. The multifaceted response of renal cells to low oxygen levels leads to diverse pathological outcomes. Targeting hypoxia-related pathways holds promise as a therapeutic approach to mitigate kidney injury and improve renal outcomes. Further research is warranted to translate these findings into effective clinical treatments for kidney diseases associated with hypoxia.

Acknowledgement

Not applicable.

Conflict of Interest

There is no conflict of interest by author.

References

1. Mittal, Bharati, Helmut Rennke and Ajay K. Singh. "The role of kidney biopsy in the management of lupus nephritis." Curr Opin Nephrol Hypertens 14 (2005): 1-8.

Google Scholar, Crossref, Indexed at

2. Bihl, Geoffrey R., Michelle Petri and Derek M. Fine. "Kidney biopsy in lupus nephritis: Look before you leap." Nephrol Dial Transplant 21 (2006): 1749-1752.

Google Scholar, Crossref, Indexed at

3. Looker, Helen C., Laura Pyle, Tim Vigers and Cameron Severn, et al. "Structural lesions on kidney biopsy in youth-onset and adult-onset type 2 diabetes." Diabetes Care 45 (2022): 436-443.

Google Scholar, Crossref, Indexed at

4. Jung, O., J. G. Schreiber, H. Geiger and T. Pedrazzini, et al. "gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension." Circulation 109 (2004): 1795-1801.

Google Scholar, Crossref, Indexed at

5. Pickering, Thomas G. "Renovascular hypertension: Etiology and pathophysiology." Semin Nucl Med 19 (1989): 79-88.

Google Scholar, Indexed at

6. Mehta, Ankit N., and Andrew Fenves. "Current opinions in renovascular hypertension." Bayl Univ Med Cent 23 (2010): 246-249.

Google Scholar, Crossref, Indexed at

7. Diaz-Crespo, Francisco, Javier Villacorta, Mercedes Acevedo and Teresa Cavero, et al. "The predictive value of kidney biopsy in renal vasculitis: A multicenter cohort study." Hum Pathol 52 (2016): 119-127.

Google Scholar, Crossref, Indexed at