Adaptive changes in GFR, tubular morphology, and transport in subtotal nephrectomized kidneys: modeling and analysis

Removal of renal mass stimulates anatomical and functional adaptations in the surviving nephrons, including elevations in single-nephron glomerular filtration rate (SNGFR) and tubular hypertrophy. A goal of this study is to assess the extent to which the concomitant increases in filtered load and tubular transport capacity preserve homeostasis of water and salt. To accomplish that goal, we developed computational models to simulate solute transport and metabolism along nephron populations in a uninephrectomized (UNX) rat and a 5/6-nephrectomized (5/6-NX) rat. Model simulations indicate that nephrectomy-induced SNGFR increase and tubular hypertrophy go a long way to normalize excretion, but alone are insufficient to fully maintain salt balance. We then identified increases in the protein density of Na+-K+-ATPase, Na+-K+-2Cl- cotransporter, Na+-Cl- cotransporter, and epithelial Na+ channel, such that the UNX and 5/6-NX models predict urine flow and urinary Na+ and K+ excretions that are similar to sham levels. The models predict that, in the UNX and 5/6-NX kidneys, fractional water and salt reabsorption is similar to sham along the initial nephron segments (i.e., from the proximal tubule to the distal convoluted tubule), with a need to further reduce Na+ reabsorption and increase K+ secretion primarily along the connecting tubules and collecting ducts to achieve balance. Additionally, the models predict that, given the substantially elevated filtered and thus transport load among each of the surviving nephrons, oxygen consumption per nephron segment in a UNX or 5/6-NX kidney increases substantially. But due to the reduced nephron population, whole animal renal oxygen consumption is lower. The efficiency of tubular Na+ transport in the UNX and 5/6-NX kidneys is predicted to be similar to sham.This research was supported by the Department of Veterans Affairs (to V. Vallon) and by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-56248 (to V. Vallon), R01-DK-106102 (A. T. Layton and V. Vallon), and the University of Alabama at Birmingham/ University of California San Diego O'Brien Center for Acute Kidney Injury Research NIH-P30-DK-079337 (to V. Vallon). (Department of Veterans Affairs; R01-DK-56248 - National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; R01-DK-106102 - National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; NIH-P30-DK-079337 - University of Alabama at Birmingham/ University of California San Diego O'Brien Center for Acute Kidney Injury Research)Accepted manuscrip

Renal potassium handling in rats with subtotal nephrectomy: modeling and analysis

We sought to decipher the mechanisms underlying the kidney's response to changes in K+ load and intake, under physiological and pathophysiological conditions. To accomplish that goal, we applied a published computational model of epithelial transport along rat nephrons in a sham rat, an uninephrectomized (UNX) rat, and a 5/6-nephrectomized (5/6-NX) rat that also considers adaptations in glomerular filtration rate and tubular growth. Model simulations of an acute K+ load indicate that elevated expression levels and activities of Na+/K+-ATPase, epithelial sodium channels, large-conductance Ca2+-activated K+ channels, and renal outer medullary K+ channels, together with downregulation of sodium-chloride cotransporters (NCC), increase K+ secretion along the connecting tubule, resulting in a >6-fold increase in urinary K+ excretion in sham rats, which substantially exceeds the filtered K+ load. In the UNX and 5/6-NX models, the acute K+ load is predicted to increase K+ excretion, but at significantly reduced levels compared with sham. Acute K+ load is accompanied by natriuresis in sham rats. Model simulations suggest that the lesser natriuretic effect observed in the nephrectomized groups may be explained by impaired NCC downregulation in these kidneys. At a single-nephron level, a high K+ intake raises K+ secretion along the connecting tubule and reabsorption along the collecting duct in sham, and even more in UNX and 5/6-NX. However, the increased K+ secretion per tubule fails to sufficiently compensate for the reduction in nephron number, such that nephrectomized rats have an impaired ability to excrete an acute or chronic K+ load.This research was supported by the Department of Veterans Affairs (V. Vallon), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants R01-DK-112042 (V. Vallon) and R01-DK-106102 (A. T. Layton and V. Vallon), and University of Alabama at Birmingham-University of California San Diego O'Brien Center for Acute Kidney Injury Research (NIDDK Grant P30-DK-079337; V. Vallon). (Department of Veterans Affairs; R01-DK-112042 - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); P30-DK-079337 - University of Alabama at Birmingham-University of California San Diego O'Brien Center for Acute Kidney Injury Research (NIDDK Grant))Accepted manuscrip

Geological Field Trips

This field trip guide organized in the framework of the Goldschmidt Conference 2013, held in Florence from August 25 to 30, 2013, is here presented. The two-days field trip, shows some of the many geological, naturalistic and cultural features in the Fiorano area (Modena), in which history, geology and passion for Ferrari come together in a perfect marriage. The first excursion day is dedicated to visit the Natural Reserve of Salse di Nirano, where the mud volcanoes, produced by the cold mud, salt water and hydrocarbons - mainly methane- can be observed. The second day is devoted to visit the Ferrari Museum and goes on at the Spezzano Castle, hosting the Ceramics Museum. Clays are, in fact, abundant in the hilly margin, where they form badlands, characteristic narrow crests washed out by running waters. In the Castle there is also a Balsamic Vinegar producing Consortium, it’s a peculiar and typical product of Modena province. The itinerary ends with the tour to Enzo Ferrari’s Birthplace at Modena

Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion.

To clarify the physiological role of Na(+)-D-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1(-/-) mice were generated and characterized phenotypically. After gavage of d-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GIP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1(-/-) mice were compared. The impact of SGLT1 on renal glucose handling was investigated by micropuncture studies. It was observed that Sglt1(-/-) mice developed a glucose-galactose malabsorption syndrome but thrive normally when fed a glucose-galactose-free diet. In wild-type mice, passage of D-glucose across the intestinal BBM was predominantly mediated by SGLT1, independent the glucose load. High glucose concentrations increased the amounts of SGLT1 and GLUT2 in the BBM, and SGLT1 was required for upregulation of GLUT2. SGLT1 was located in luminal membranes of cells immunopositive for GIP and GLP-1, and Sglt1(-/-) mice exhibited reduced glucose-triggered GIP and GLP-1 levels. In the kidney, SGLT1 reabsorbed ∼3% of the filtered glucose under normoglycemic conditions. The data indicate that SGLT1 is 1) pivotal for intestinal mass absorption of d-glucose, 2) triggers the glucose-induced secretion of GIP and GLP-1, and 3) triggers the upregulation of GLUT2

Renoprotective Effects of SGLT2 Inhibitors.

SGLT2 inhibitors can protect the kidneys of patients with and without type 2 diabetes from failing. This includes blood glucose dependent and independent mechanisms. SGLT2 inhibitors lower glomerular pressure and filtration, thereby reducing the physical stress on the filtration barrier and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular glucotoxicity and improved mitochondrial function and autophagy, can reduce proinflammatory and profibrotic signaling and preserve tubular function and GFR in long term. By shifting transport downstream, SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves oxygen delivery to the kidney and other organs

Tubular Transport in Acute Kidney Injury: Relevance for Diagnosis, Prognosis and Intervention

The clinical diagnosis and recovery of acute kidney injury (AKI) are mainly based on the rapid decline of glomerular filtration rate (GFR) and its subsequent recovery. The factors that determine kidney recovery and reduce the risk of subsequent progression to chronic kidney disease (CKD), however, are poorly understood. Thus, there is a need to better define the magnitude and time pattern of changes in kidney function during AKI and its recovery that go beyond GFR. Tubular transport regulates body homeostasis and the associated transport work is a primary determinant of the kidneys' energy needs. The tubular system is at the center of the pathophysiology of AKI and its recovery. In particular, proximal tubules and thick ascending limbs have been proposed to act as sensors, effectors and injury recipients of AKI stimuli. Surprisingly little attention has been given to aspects of tubular transport function in AKI and the relevance for kidney recovery. This review aims to outline changes in tubular transport function in AKI, discusses their potential consequences and relevance for the diagnosis and prognosis of AKI and its recovery, including changes in GFR, and poses the question whether tubular transport provides an opportunity for intervention to rest the tubular system, which may have consequences for the progression to CKD. © 2016 S. Karger AG, Basel