Recent advances in kidney research

Abstract

The kidney, pivotal for maintaining systemic homeostasis, remains one of the crucial target organs of physiological research, which has unveiled the intricate molecular mechanisms governing its function. In the following, we will highlight recent developments in the field of kidney research published in Acta Physiologica. Both original research articles in the field of kidney research and reviews have been considered, providing an overview of some recent breakthroughs in renal physiology, encompassing glomerular filtration dynamics, tubular transport mechanisms, hormonal regulation, and the genetic and environmental determinants of renal health. The general scope of the articles reaches from basic research that helps to understand pathophysiology better to contributions that might have a potential clinical impact in the near future.

The kidney has several endocrine roles, secreting both hormones and humoral factors of, for example, the renin- angiotensin system (RAS), erythropoietin (EPO), and 1,25 dihydroxy vitamin D3. It is critically involved in vitamin D and phosphate homeostasis, which are both modulated by the by fibroblast growth factor 23 (FGF23).¹ In this study by Feger et al. the effect of short term fasting on FGF23 were analyzed. The experiments were performed in cell cultures of rat myocytes as well as in mice that were fasted overnight. The authors found higher β-hydroxybutyrate and FGF23 serum levels in fasted mice in contrast to the fed animals. Future studies are needed to decipher whether these observations from short term fasting are of clinical and practical relevance as blood tests of FGF23 become more and more relevant as biomarkers for monitoring diseases. Parathyroid hormone, in an intricately orchestrated interplay, controls calcium, phosphate and vitamin D levels. Alexander and Dimke.² provide an in-depth review of PTH signaling along the renal tubule and its role in normal kidney function and pathophysiology.

The kidneys play a crucial role in systemic immune response reactions to infectious agents by filtering toxins and waste products from the blood, aiding in the regulation of fluid balance, and maintaining electrolyte equilibrium. In sepsis, the kidneys can be significantly impacted, leading to acute kidney injury (AKI) due to the body's response to infection, impaired blood flow, and the release of inflammatory mediators. Exercise has been suggested to have an protective effect in sepsis-associated organ dysfunction.³ In a study by Xu et al.³ the authors wanted to test that this effect is related to R-spondin 3. To this end the authors used inducible endothelial cell-specific RSPO3 knock out mice in a LPS-induced acute kidney injury model in trained and untrained mice. The authors find that aerobic exercise-trained mice were more resistant to LPS-induced body weight loss and hypothermia and had a significant higher survival rate than sedentary mice exposed to LPS. The researchers conclude that an Increased renal expression of RSPO3 contributes to aerobic exercise-induced protection against LPS-induced renal endothelial hyperpermeability and AKI by suppressing MMPs-mediated disruption of glycocalyx and tight and adherens junctions.³ Since the authors did not investigate humans the clinical relevance to humans of those findings are yet to be determined.

Sepsis was also a topic of a work by Betrie et al.⁴ Here the researchers investigated how the drug tempol acts on the kidney during ovine Gram-negative sepsis. Tempol is used as an antioxidant and anti-inflammatory drug in this study. Betie et al analyzed the effect of tempol on kidney function and find that renal medullary hypoperfusion, hypoxia and acute kidney injury was prevented by tempol. The authors claim to have identified potential mechanisms for the beneficial effects of tempol infusion in patients with septic acute kidney injury, including prevention of overexpression of TNF-α in the renal cortex and inhibition of eNOS uncoupling in the renal medulla. Increased nitric oxide availability, which may have contributed to the improvement in renal function observed with tempol infusion. Further investigation is needed to assess whether the results are relevant also in human pathophysiology.

There are a number of molecular tools to study cell function in their interaction in tissue structures. Cell lineage tracing is a powerful technique used in kidney research to elucidate the developmental origins and lineage relationships of different cell types within the kidney. By tracking the fate of individual cells or their progeny over time, researchers can gain insights into kidney development, regeneration, disease progression, and the effectiveness of therapeutic interventions. In an interesting work by Nagalakshmi et al.⁵ the authors wanted to solve the question whether changes in renin expression during urethral obstruction are responsible for the progression of kidney damage, repair, or regeneration. The model the researchers use here is a simulation of the obstructive nephropathy in the developing human foetus. They combined lineage tracing by tagging the cells of the renin lineage with green fluorescent protein GFP and with an reversible unilateral ureteral obstruction (pUUO) in neonatal mice. In addition to the tagging they used an ablation strategy of the renin producing cells by cell-specific expression of Diphtheria Toxin Subunit A (DTA). They find an increased renin positive are in the obstructed kidneys, where the relief of the obstruction reversed the increase. The DTA expressing animals did not show the increase in renin producing cells. Most interesting, the reduction in cells of the renin lineage significantly compromised the kidney's ability to recover from the damage after the release of obstruction. The authors claim that the cells of the renin lineage play an important role in the regeneration of the kidney after temporary obstruction.⁵

Systemic immunosuppression can have profound effects on the kidney, leading to increased susceptibility to infections, drug-induced nephrotoxicity, and heightened risk of immune-mediated renal disorders. Cyclosporin A (CsA) is a widely used immunosuppressive drug that causes hypertension and hyperkalemia.⁶ Interestingly, the kidney has been shown to be responsible for the development of hyperkalemic hypertension in this context. In this work by Gao et al the researchers have teste the hypotheses whether CsA induces the activation of thiazide-sensitive NaCl cotransporter (NCC) by stimulating the basolateral Kir4.1/Kir5.1 channel in the distal convoluted tubule (DCT). The methods they employed included electrophysiology, immunoblotting and animal experiments, namely kidney-specific Kir4.1 knockout (KS-Kir4.1 KO) mice and their wild type controls. The single-channel patch clamp experiment demonstrated that CsA stimulated the basolateral 40 pS K+ channel in the DCT (distal convoluted tubule). This stimulation was accompanied by an increase in phosphorylated NCC (pNCC) levels, suggesting that Kir4.1 is required to mediate CsA effects on NCC function. In the animal experiments the long-term CsA infusion (14 days) increased blood pressure, plasma K+ concentration, and total NCC or pNCC abundance in WT mice but these effects were blunted in KS-Kir4.1 KO mice. The authors conclude that CsA stimulates basolateral K+ channel activity in the distal convoluted tubule and that Kir4.1 is essential for CsA-induced thiazide-sensitive NaCl cotransporter activation and hyperkalemic hypertension. Further the authors suggest that pharmacological targeting of Kir4.1 may be a potential therapeutic strategy for calcineurin inhibitor induced hyperkalemic hypertension. In addition to immunosuppressive drugs, cancer chemotherapy also adversely affects the kidney. In addition, it is also highly dependent on an accurate estimation of kidney function, which is the focus of a recent work by Claudel et al.⁷

Tightly controlled epithelial transport mechanisms in the kidney are fundamental for regulating the balance of electrolytes, water, and waste products crucial for maintaining proper physiological function and systemic homeostasis.⁸ One of the important molecules might be the Two-pore channels protein 1 (TPC1) which was the focus of the work of Just et al.⁹ The methofds here include immunohistological stainings as well as functional studies in TPC1-deficient mice and their controls. The authors find that TPC1 is involved in regulating phosphate excretion through parathyroid hormone (PTH) signaling. In mice lacking TPC1, the response to PTH-induced phosphate excretion was prolonged and exaggerated compared to wildtype mice. When exposed to sodium bicarbonate TPC1-deficient mice showed a similar increase in phosphate excretion as their wildtype counterparts. However, when exposed to ammonium chloride, which is known to deplete PTH levels and exert an acid–base compensatory effect, TPC1-deficient mice showed a delayed recovery in phosphate excretion compared to wildtype littermates. The authors conclude that TPC1 is expressed subapically in the proximal but not distal tubule and plays functionally an important role in the adaptation of proximal tubular phosphate reabsorption towards enhanced, but not reduced absorption.⁹ Adella et al.¹⁰ recently published a conclusive analysis on the role of mTOR signaling in tubular solute transport.

Tissue hypoxia is an early key feature of acute kidney injury. The rapid early assessment of renal oxygenation using magnetic resonance imaging (MRI) markers¹¹ might reveal insights into renal pathophysiology.¹² In this methodological study that appeared in Acta Physiologica Cantow et al investigate different physiological scenarios to the relaxation parameters T1 and T2 in MRI in rats and combine this with a biophysical model was used to estimate changes in O₂ saturation of hemoglobin from changes in T2* and kidney size. The authors conclude from their results that monitoring kidney size is relevant for the interpretation of acute renal oxygenation as determined by T1 and T2, and therefore, kidney size needs to be measured also in human studies when used for oxygenation measurements in clinical studies.

The relationship between the kidney and the heart and cardiovascular system in pathophysiology is intricate, with dysfunction in one organ often leading to adverse effects on the other due to shared risk factors, hemodynamic alterations, and neurohormonal interactions, contributing to the development and progression of cardiorenal syndrome. Impaired kidney function such as modeled by 5/6 nephrectomy in combination with a high-phosphate diet may lead to atrial fibrillation.¹³ This is of relevance to human pathophysiology since atrial fibrillation increases the risk of strokes and by this of disability and that structured management of patients with atrial fibrillation would reduce the risk of stroke and other adverse events.¹⁴ Endothelial to mesenchymal transition, whereby endothelial cells undergo molecular events leading to a change in phenotype towards mesenchymal cells, is another pathophysiological process overlapping between the cardiovascular system and the kidney. Endothelial cell plasticity and change towards a mesenchymal phenotype is a focus of a recent work by Pohl et al.¹⁵ Layton et al. explored how SGLT2 inhibitors, which reduce the risk of cardiovascular mortality and morbidity, exert their beneficial effects on the progression of chronic kidney disease.¹⁶

In addition to original research articles, several recent review articles highlight developments in renal physiology and pathophysiology pertaining to physiological feedback loop mechanisms, such as glomerular crosstalk mechanisms and circadian rhythm. Firstly,¹⁷ hypothesizes that the complex regulatory network around the regulation of glomerular microcirculation contributes to renal functional reserve and is affected in physiological processes such as renal function during pregnancy as well as developing diabetes mellitus and acute kidney injury. Mesangial cells, having been proposed to both remove pathogens from the glomerulus and deposit extraglomerular material, contribute to renal cellular immune responses and glomerular cell-to-cell signaling,¹⁸ are notably important mediators of glomerular crosstalk.¹⁹ Felten et al.²⁰ looked at circadian rhythm disruption in ICU patients with a focus on the role of individual organs, and the potential of rhythm-stabilizing interventions to enhance and accelerate clinical recovery.

Several of these advancements have the potential to facilitate the development of targeted therapeutic interventions and diagnostic modalities for renal disorders.

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