Tubuloglomerular Feedback Research Articles

Significance of SGLT2 inhibitors: lessons from renal clinical outcomes in patients with type 2 diabetes and basic researches.

Diabetic kidney disease (DKD), a microvascular complication of diabetes, has been the leading cause of end-stage kidney disease (ESKD). Accordingly, patients with type 2 diabetes mellitus (T2DM) develop renal damage due to multiple metabolic and cardiorenal disease-related risk factors, including hyperglycemia, hypertension, dyslipidemia, hyperuricemia, and overnutrition/obesity. Despite multifactorial management including the administration of renin-angiotensin system inhibitors, patients often do not experience sufficient suppression of DKD progression and, thus, remain at risk for ESKD. Recent studies on cardiovascular outcomes among patients with T2DM have clearly shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin, canagliflozin, and dapagliflozin, have cardiorenal protective effects apart from their glucose-lowering effects. In particular, SGLT2 inhibitors have been found to improve renal outcomes, including ESKD, by slowing renal function decline and reducing urinary albumin excretion through their class effect. The proposed mechanisms for the renoprotective effects of SGLT2 inhibitors include the action of tubulo-glomerular feedback system and attenuation of hypoxia and metabolic stress in proximal tubular cells mediated through the inhibition of excessive glucose and sodium reabsorption, increased erythropoiesis, or increased ketone body production.

SO022EVALUATION OF GLOMERULAR HEMODYNAMIC CHANGES BY SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING TECHNIQUES

Abstract Background and Aims In recent clinical trials, the SGLT2 inhibitor (SGLT2i) slowed the progression of kidney disease compared with the placebo in patients with type 2 diabetes. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). We have successfully developed the novel method to measure single-nephron GFR (SNGFR) in mice using multiphoton laser microscopy and demonstrated that the adenosine/adenosine A1 receptor (A1aR) pathway plays a pivotal role in the TGF mechanism in the type 1 diabetic model, Akita mice (Kengo Kidokoro, David Z. I. Cherney et al. Circulation. 2019). It has been suggested that the mechanism of improvement effects in glomerular hyperfiltration by SGLT2i is different in type 1 diabetes and type 2 diabetes. However, the detailed regulatory mechanism of GFR by SGLT2i is not fully understood in type 2 diabetes. This study aims to clarify the effects of SGLT2i on glomerular hemodynamics in type 2 diabetic rats. Method Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg) group, and insulin group. Results SNGFR in the ZDF group was significantly higher than in the ZL group. The diameter of the afferent arteriole and efferent arteriole was also wider in ZDF rats than in ZL rats. The SNGFR and diameter of the afferent arteriole were significantly decreased after a single-dose administration of SGLT2i in ZDF. However, there was no significant diameter change in the efferent arteriole. Moreover, a decrease of SNGFR was not observed in the A1aR antagonist group after SGLT2i administration. Urinary excretions of glucose and sodium showed a similar pattern in the SGLT2i and SGLT2i+ A1aR antagonist groups. Conclusion The adenosine/A1aR pathway plays an important role in the regulation of the tonus of the afferent arteriole and is involved in the suppression of glomerular hyperfiltration by SGLT2 inhibition in type 2 diabetes.

Functional Relevancies of Trans-Differentiation in the Juxtaglomerular Apparatus of Rat Kidney.

Glomerular filtration rate is controlled by the contractile effect of angiotensin II on afferent and efferent arterioles. The renin positivity of the afferent arterioles depends on tubuloglomerular feedback via the macula densa (MD) and short loop feedback via the afferent arteriolar endothelia. The renin-producing cells are trans-differentiated from smooth muscle cells (SMCs) of mainly the afferent arterioles, the MD cells are trans-differentiated from the neighboring tubular cells, and the high-permeability endothelial cells are trans-differentiated from normal permeability endothelial cells facing the renin-negative part of the afferent arterioles. All of the trans-differentiations depend on the activity of the renin-angiotensin system (RAS). The distribution of AT1 receptors for angiotensin II expresses the contractile effects of angiotensin II on renin-negative SMCs and the negative effect on trans-differentiation of renin-positive SMCs and MD cells. The purpose of this review is to summarize the stereological data of molecules like angiotensin II AT1 receptors, L-type calcium channels, and renin receptors in the juxtaglomerular apparatus of normal and STZ-induced diabetic rat kidneys, thus showing their functional relevancies on trans-differentiation among the juxtaglomerular apparatus’ elements.

SO021EFFECTS OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITOR, CANAGLIFLOZIN ON GLOMERULAR HYPERFILTRATION AND OXIDATIVE STRESS IN MICE WITH TYPE 2 DIABETES

Abstract Background and Aims In most developed countries, diabetic kidney disease (DKD) is the most common cause of chronic kidney disease, which can lead to end-stage renal disease. In recent clinical trials, sodium–glucose cotransporter 2 inhibitors (SGLT2is) slowed the progression of kidney disease as compared with a placebo in patients with type 2 diabetes. One of the main mechanisms of the renoprotective effects of SCLT2is in DKD is considered the ability of these inhibitors to improve glomerular hyperfiltration. We previously demonstrated that the adenosine/adenosine A1 receptor pathway played a pivotal role in the tubuloglomerular feedback(TGF) system in a type 1 diabetic model, Akita mice (Circulation, 2019). We also reported that increased oxidative stress was involved in the pathogenesis of diabetic vascular complications. Uncoupling of endothelial nitric oxide (NO) synthase (eNOS) via oxidation of tetrahydrobiopterin (BH4), a cofactor required for NO production, played a major role in generation of oxidative stress (AJPRP, 2005; JASN, 2013). In the present study, we explored the renal protective effects of SGLT2 inhibition, with a focus on glomerular hemodynamics and glomerular oxidative stress. Method This study used type 2 diabetic db/db mice and db/m+ mice as a control (male, 8wk old). We developed a novel method to measure the glomerular filtration rate of single nephrons (SNGFRs) in mice using multiphoton laser microscopy. In the first experiment, we measured the SNGFRs in 12 wk-old db/db and db/m+ mice to confirm glomerular hyperfiltration. Next, we evaluated the SNGFRs change before and after the administration of a single dose of canagliflozin (CANA) (10 mg/kg). The SNGFRs, glomerular permeability of macromolecules, glomerular reactive oxygen species (ROS) and NO production, and tetrahydrobiopterin (BH4) level in serum and kidney were evaluated after the CANA treatment for 8 wk. Finally, human glomerular endothelial cells (hGECs) were exposed to normal glucose (5 mmol/L), high glucose (30 mmol/L of D-glucose), or a hyperosmotic control (5 mmol/L of D-glucose plus 25 mmol/L of L-glucose) in the presence or absence of CANA (10 μmol/L). Results The CANA treatment ameliorated glomerular hyperfiltration in the db/db mice. In the db/db mice, glomerulus ROS production increased, and NO production decreased as compared with the levels in the control mice. CANA improved the imbalance between ROS and NO production. The serum and kidney concentrations of BH4 declined in the non-treated db/db mice, whereas the CANA treatment preserved the BH4 level. Leakage of 70-kD FITC-labeled albumin into the urinary space was observed in the db/db mice. The CANA treatment reduced the amount of FITC-labeled albumin in the urinary space of the db/db mice. The CANA treatment also alleviated vascular endothelial damage in glomeruli. BH4 levels decreased in the hGECs exposed to high glucose. CANA did not improved BH4 level in the hGECs exposed to high glucose. Conclusion SGLT2i ameliorated glomerular hyperfiltration, preserving BH4 levels and improving the glomerular ROS/NO imbalance in type 2 diabetic mice.

Hyperreninemia and low total body water may contribute to acute kidney injury in COVID-19 patients in intensive care.

Corona virus disease 2019 (COVID-19) is primarily associated with respiratory failure but both renal and circulatory failure is a common occurrence in patients with more severe disease that require intensive care [1], or die of the disease [2]. The developing guidelines for treating COVID-19 patients in intensive care suggest a frugal fluid strategy to avoid acute respiratory distress syndrome [3]. However, this may leave fluid resuscitation insufficient for renal and circulatory function increasing the risk of acute kidney injury (AKI). This case series is part of a study approved by the National Ethical Review Agency (EPM; No. 2020-01623). Informed consent was obtained from the patient, or next of kin if the patient was unable give consent. The Declaration of Helsinki and its subsequent revisions were followed. Plasma renin as well as biochemistry was collected with routine clinical sampling in the morning and analysed by the clinical chemistry department at Uppsala University Hospital according to standard procedures. We present a case series where we found pronounced hyperreninemia in association with hypernatremia, hyperchloremia and low glomerular filtration rate primarily in patients late in their intensive care stay (Table 1).TABLE 1: Biochemistry of patients ordered by days after intensive care admissionThere are several possible explanations for these findings. One is that the ACE2 affinity of SARS-COV-2 [4] directly affects the renin–angiotensin system and drives renin secretion despite high circulating sodium chloride. However, the association with high sodium and chloride suggests extra cellular fluid contraction and for the kidneys excessively restrictive fluid therapy with hypovolemia and water deficit. An alternative is a virus-induced or cytokine-induced renin release acting as a pseudohypovolemia. In this setting, the combination of high renin and high chloride may interact through the tubuloglomerular feedback system to supress glomerular filtration rate, thereby contributing to the development of AKI in COVID-19 patients. The data may also suggest that this is an iatrogenic cause during intensive care as we do not see it in recently admitted patients. The restrictive use of fluid resuscitation in COVID-19 may be beneficial for the lungs but may also promote AKI. However, if coagulopathy and microthrombi contribute importantly to the progression as has been suggested, low circulating volume may impair pulmonary flow regulation and thereby oxygenation as well. Significantly, the use of renin–angiotensin blockers have been found to be associated with improved outcome [5], and the present data may suggest that ameliorating the overactivation of the renin–angiotensin system may be a mechanism. In conclusion, patients with COVID-19 tend to develop hyperreninemia combined with hypernatremia and hyperchloremia in intensive care, which is associated with AKI in a way that suggests hypovolemia or pseudohypovolemia. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

High-protein diet: A barrier to the nephroprotective effects of sodium-glucose co-transporter-2 inhibitors?

Glomerular hyperfiltration is a common finding in patients with diabetes and poor glycaemic control; whole-kidney hyperfiltration, with glomerular filtration rate (GFR) values above normal, should be differentiated from single nephron hyperfiltration, consequent to nephron loss and compensatory hyperfiltration of the remnant nephrons. This is the result of an imbalance between the vascular tone of the afferent and efferent arterioles. Hormonal influences and/or an impaired tubuloglomerular feedback (TGF) system, because of excessive sodium (Na+ ) and glucose reabsorption in the proximal tubule, contribute to determine hyperfiltration. Sodium-glucose co-transporter-2 inhibitors (SGLT2is), by decreasing Na+ reabsorption and increasing the delivery of Na+ to the macula densa, lead to normalization of TGF, and, consequently, decrease GFR (both whole and single nephron). High-protein diets are popular among patients with type 1 and type 2 diabetes; importantly, 80% of the amino acids are also reabsorbed in the proximal tubule of the nephron and are transported by symporters that use the electro-chemical gradient of Na+ . Indeed, an acute protein load is associated with increased Na+ reabsorption and an increase in GFR. Here, we hypothesize that high-protein diets, by increasing Na+ reabsorption and GFR, may offset the positive renal effects of SGLT2is.

Reactive oxygen species in renal vascular function.

Reactive oxygen species (ROS) are produced by the aerobic metabolism. The imbalance between production of ROS and antioxidant defence in any cell compartment is associated with cell damage and may play an important role in the pathogenesis of renal disease. NADPH oxidase (NOX) family is the major ROS source in the vasculature and modulates renal perfusion. Upregulation of Ang II and adenosine activates NOX via AT1R and A1R in renal microvessels, leading to superoxide production. Oxidative stress in the kidney prompts renal vascular remodelling and increases preglomerular resistance. These are key elements in hypertension, acute and chronic kidney injury, as well as diabetic nephropathy. Renal afferent arterioles (Af), the primary resistance vessel in the kidney, fine tune renal hemodynamics and impact on blood pressure. Vice versa, ROS increase hypertension and diabetes, resulting in upregulation of Af vasoconstriction, enhancement of myogenic responses and change of tubuloglomerular feedback (TGF), which further promotes hypertension and diabetic nephropathy. In the following, we highlight oxidative stress in the function and dysfunction of renal hemodynamics. The renal microcirculatory alterations brought about by ROS importantly contribute to the pathophysiology of kidney injury, hypertension and diabetes.

Kidney alkalization increases macula densa NOS1β expression and improves transplanted renal graft function

Ischemia‐reperfusion injury (IRI) is a major hurdle for the survival of transplanted grafts. Currently, there are no effective strategies for prevention and treatment of IRI during kidney transplantation (KTX). Neuronal NO synthase beta (NOS1β) is the primary splice variant of NOS1 in macula densa (MD) and contributes to most of the MD‐NO generation, which blunts tubuloglomerular feedback (TGF) response and increase GFR, which is one of the important factors in evaluation of renal function. While TGF response modulated by NOS1β has been demonstrated to play an essential role in the long‐term control of hemodynamics, the role of NOS1 in the MD in the prevention of IRI and protection of transplanted graft function remains unknown.KTX was performed in C57BL/6 mice. The expression of NOS1 and graft function were evaluated. To test the response of NOS1 to the tubular pH, the mice were given bicarbonate or NH4Cl for two weeks. Blood, urine pH and expression of NOS1 were measured. KTX were performed after the treatment. Graft injury and function were evaluated again. To further investigate the role of the NOS1 in the protection of the graft function, we repeated the above experiments in kidney specific NOS1 knockout (KO) mice and compared the results with C57BL/6 mice.The control recipients showed moderate graft injury with plasma creatinine (Pcr) of 0.68 ± 0.13 mg/dl and reduced graft function indicated by 23% decrease in GFR at 5 days after KTX. NOS1β expression decreased by 60%. TGF response was measured by micropuncture which was 4.1 ± 0.3 mmHg for sham‐operated mice and 7.2 ± 0.9 mmHg for KTX mice. These data indicated that decreased NOS1β expression may contribute to the decrease of GFR and deterioration in graft function by enhanced TGF response. KO recipients showed more severe graft injury with the Pcr of 1.07±0.14mg/dl which demonstrated that deletion of NOS1 from macula densa significantly aggravated renal graft injury.The pH‐NOS activity response curve showed that NOS1 was sensitive to tubular pH with the optimal pH of 8.0. Bicarbonate treatment increased NOS1 expression in macula densa by 65% while NH4Cl intake decreased the NOS1 expression by 40%.KTX were performed in C57BL/6 and KO mice after two weeks treatment of bicarbonate or NH4Cl. Pcr levels were about 30% and 100% lower in bicarbonate‐treated group than H2O and NH4Cl groups, respectively, indicating that bicarbonate treatment significantly alleviated graft injury. However, there were no significant differences in the graft injury for the KO mice among different groups.In summary, NOS1β expression in the macula densa decreases after KTX, which enhances TGF responsiveness and contributes to the decrease in GFR and decline of graft function. Rescue of NOS1β in the macula densa by renal alkalization decreases kidney injury and improves transplanted graft functions.

The tubular hypothesis of nephron filtration and diabetic kidney disease.

Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.

Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors.

Empaglifolzin, canagliflozin, and dapagliflozin are SGLT2 (sodium-glucose linked transporter type 2) inhibitors for treatment of type 2 diabetes mellitus that also reduce blood pressure, mortality, and cardiovascular disease and slow the loss of glomerular filtration rate. SGLT2 inhibitors inhibit the coupled reabsorption of sodium and glucose from the proximal tubules, thereby increasing renal glucose and sodium excretion, but they have more widespread renal effects, including inhibition of the sodium:proton exchanger. They increase the delivery of sodium to the loop of Henle and can thereby activate the tubuloglomerular feedback response to correct glomerular hyperfiltration. There are multiple potential mechanisms whereby these drugs lower blood pressure and preserve kidney function that are the focus of this review.

Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework.

Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphate-activated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes.

Upregulation of renal Na–K–2Cl cotransporter 2 in obese diabetes mellitus via a vasopressin receptor 2-dependent pathway

Na–K–2Cl cotransporter 2 (NKCC2) in thick ascending limb (TAL) in the kidney plays a central role in tubuloglomerular feedback (TGF) system by sensing NaCl delivery to the distal tubules. Although accumulating data indicate that dysregulated TGF contributes to the progression of diabetic complications, the regulation of NKCC2 in diabetes mellitus (DM) remains unclear. We here show that NKCC2 is overactivated via a vasopressin receptor 2 (V2R)-dependent mechanism in db/db mice, a mouse model of obese DM. Compared with db/+ mice, we found that both aquaporin 2 and NKCC2 levels were significantly increased in the kidney in db/db mice. Immunohistochemical analysis of V2R and NKCC2 in the kidney demonstrated that V2R is present in the TAL, as well as in the collecting duct. Moreover, the administration of tolvaptan, a selective V2R antagonist, sharply decreased aquaporin 2 and NKCC2 in db/db mice, confirming the causal role of V2R signaling in NKCC2 induction in this model. Although tolvaptan reduced aquaporin 2 abundance also in db/+ mice, its effect on NKCC2 was modest compared with db/db mice. In total kidney lysates, uromodulin expression was not altered between db/+ and db/db mice, suggesting that V2R signaling alters NKCC2 without altering uromodulin levels. These data implicate the dysregulation of NKCC2 in the pathophysiology of type 2 DM, and underscore the complex nature of fluid volume disorders in diabetic kidney disease.

Clinical Implications

Clinical Implications

Influence of connexin45 on renal autoregulation.

Renal autoregulation is mediated by the myogenic response and tubuloglomerular feedback (TGF) working in concert to maintain renal blood flow and glomerular filtration rate despite fluctuations in renal perfusion pressure. Intercellular communication through gap junctions may play a role in renal autoregulation. We examine if one of the building blocks in gap junctions, connexin45 (Cx45), which is expressed in vascular smooth muscle cells, has an influence on renal autoregulatory efficiency. The isolated perfused juxtamedullary nephron preparation was used to measure afferent arteriolar diameter changes in response to acute changes in renal perfusion pressure. In segmental arteries, pressure myography was used to study diameter changes in response to pressure changes. Wire myography was used to study vasoconstrictor and vasodilator responses. A mathematical model of the vascular wall was applied to interpret experimental data. We found a significant reduction in the afferent arteriolar constriction in response to acute pressure increases in Cx45 knockout (KO) mice compared with wild-type (WT) mice. Abolition of TGF caused a parallel upward shift in the autoregulation curve of WT animals but had no effect in KO animals, which is compatible with TGF providing a basal tonic contribution in afferent arterioles whereas Cx45 KO animals were functionally papillectomized. Analysis showed a shift toward lower stress sensitivity in afferent arterioles from Cx45 KO animals, indicating that the absence of Cx45 may also affect myogenic properties. Finally, loss of Cx45 in vascular smooth muscle cells appeared to associate with a change in both structure and passive properties of the vascular wall.

Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease.

In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be controlled. Therefore, further study of the pathogenesis of DKD and improvements in DKD treatment are crucial for prognosis. Traditional studies have shown that podocyte injury plays an important role in this process. Recently, it has been found that glomerulotubular balance and tubuloglomerular feedback (TGF) may be involved in the progression of DKD. Glomerulotubular balance is the specific gravity absorption of the glomerular ultrafiltrate by the proximal tubules, which absorbs only 65% to 70% of the ultrafiltrate. This ensures that the urine volume will not change much regardless of whether the glomerular filtration rate (GFR) increases or decreases. TGF is one of the significant mechanisms of renal blood flow and self‐regulation of GFR, but how they participate in the development of DKD in the pathological state and the specific mechanism is not clear. Injury to tubular epithelial cells (TECs) is the key link in DKD. Additionally, injury to glomerular endothelial cells (GECs) plays a key role in the early occurrence and development of DKD. However, TECs and GECs are close to each other in anatomical position and can crosstalk with each other, which may affect the development of DKD. Therefore, the purpose of this review was to summarize the current knowledge on the crosstalk between TECs and GECs in the pathogenesis of DKD and to highlight specific clinical and potential therapeutic strategies.

Renoprotective effects of sodium-glucose cotransporter-2 inhibitors and underlying mechanisms.

Emerging data have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent cardiovascular events, especially heart failure-associated endpoints. Cardiovascular outcome trials have also suggested their renoprotective effects. One large clinical trial investigated renal primary endpoints and demonstrated that SGLT2 inhibitors slowed the progression of diabetic kidney disease (DKD). This review summarizes clinical trial data on renal outcomes and discusses potential underlying mechanisms. The EMPA-REG, CANVAS, and DECLARE-TIMI 58 studies revealed that SGLT2 inhibitors reduce the risk of cardiovascular events and concomitantly suggested that these drugs slow the progression of kidney disease in type 2 diabetes. The CREDENCE trial on patients with high-risk type 2 diabetes and chronic kidney disease demonstrated that canagliflozin treatment reduced the relative risk of a composite outcome, including end-stage kidney disease, serum creatinine doubling, and renal/cardiovascular death, by 30% in these patients. Animal experiments revealed that oxidative stress, inflammation, fibrosis, and tubuloglomerular feedback are underlying renoprotective mechanisms behind SGLT2 inhibitors. Recent clinical trials have established the renoprotective effects of SGLT2 inhibitors. Further investigations on mechanisms of these renoprotective effects will provide deeper insights and understanding of pathogenetic properties of DKD.

Renal Nerve Deafferentation Attenuates the Fall in GFR during Intravenous Infusion of Furosemide in Anesthetized Rats

Introduction: Furosemide reduces the glomerular filtration rate (GFR) and increases the renal vascular resistance (RVR) despite inhibiting tubuloglomerular feedback but increases proximal tubule pressure, renin release, and renal nerve activity. Objective: This study tested the hypothesis that the fall in GFR with furosemide is due to volume depletion or activation of angiotensin type 1 (AT1) receptors or renal nerves. Methods: Furosemide was infused for 60 min at 1.0 mg·kg⁻¹·h⁻¹ in groups of 5–8 anesthetized rats. Additional groups received intravenous volume replacement to prevent fluid and Na⁺ losses or volume replacement plus losartan or plus sham denervation or plus renal denervation or renal nerve deafferentation. Results: At 60 min of infusion, furosemide alone reduced the GFR (–37 ± 4%; p < 0.01). This fall was not prevented by volume replacement or pretreatment with losartan, although losartan moderated the increase in RVR with furosemide (+44 ± 3 vs. +82 ± 7%; p < 0.01). Whereas the GFR fell after furosemide in rats after sham procedure (–31 ± 2%), it was not changed significantly after prior renal deafferentation. Proximal tubule pressure increased significantly but returned towards baseline over 60 min of furosemide, while urine output remained elevated, and GFR and renal blood flow depressed. Conclusions: The fall in GFR over 60 min of furosemide infusion is independent of volume depletion or activation of AT1 receptors but is largely dependent on renal afferent nerves.

Cardiorenal Syndrome in Type 2 Diabetes Mellitus - Rational Use of Sodium-glucose Cotransporter-2 Inhibitors.

Cardiorenal syndrome (CRS) in people with type 2 diabetes mellitus (T2DM) illustrates the bidirectional link between the heart and the kidneys, with acute or chronic dysfunction of one organ adversely impacting the function of the other. Of the five subtypes identified, type 1 and 2 CRS occur because of the adverse impact of cardiac conditions on the kidneys. Type 3 and 4 occur when renal conditions affect the heart, and in type 5, systemic conditions impact the heart and kidneys concurrently. The cardiovascular and renoprotective benefits evidenced with sodium-glucose cotransporter-2 (SGLT2) inhibitors make them a potential choice in the management of CRS. Cardiovascular protection is mediated by a reduction in cardiac workload, blood pressure, and body weight; with improvement in lipid profile, uric acid levels, and adaptive ketogenesis process. Renoprotection is facilitated by reduction in albuminuria and hypoxic stress, and restoration of tubuloglomerular feedback. The favourable effect on cardiovascular complications and death, as well as renal complications and progression to end-stage kidney disease, has been confirmed in clinical trials. Guidelines endorse first-line use of SGLT2 inhibitors after metformin in patients with T2DM with high cardiovascular risk, chronic kidney disease or both. Since most trials with SGLT2 inhibitors excluded subjects with acute illness, patients with CRS subtypes 1 and 3 have not been studied adequately, making SGLT2 initiation in clinical practice challenging. Ongoing trials may provide evidence for SGLT2 inhibitor use in CRS. This review aims to enhance understanding of CRS and provide guidance for judicious use of SGLT2 inhibitors in T2DM.

Do sodium-glucose cotransporter-2 inhibitors affect renal hemodynamics by different mechanisms in type 1 and type 2 diabetes?

Cardiovascular and renal outcome trials demonstrate nephroprotection with sodium-glucose cotransporter-2 inhibitors in people with type 2 diabetes. Attenuation of hyperfiltration is believed to be responsible for the nephroprotection, and studies in young adults with type 1 diabetes suggest that afferent arteriolar vasoconstriction induced by a tubuloglomerular feedback mechanism may be responsible for this effect. The study by van Bommel etal. suggests that this mechanism may not hold true in older adults with type 2 diabetes, who instead attenuate elevated glomerular filtration rate via post-glomerular vasodilation.