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Archive for the '[Biology&Environment]' category

#ExpBio - Cannaboids and the Injured Kidney

Apr 26 2017 Published by whizbang under [Biology&Environment], [Medicine&Pharma], ExpBio 2017 Cannabinoid receptors exist in many tissues, not just those fun neurological areas we all think about. The kidney contains type 2 receptors (CB2), and experimental data suggests they might play a role in acute kidney injury. With unilateral ischemia-reperfusion injury (IRI) CB2 receptors are dramatically upregulated after 72 hours, returning to baseline after 168 hours (7 days).

Could activating these receptors help the kidney heal itself?

Pressly et al used a novel CB2 agonist (SMM-295) in bilateral IRI, administering it just after ischemia and every 24 hours after. Kidney function and structure were examined 24 and 48 hours after injury.

Animals treated with SMM-295 did not have elevated creatinines after IRI. NGAL, a marker of tubular damage, also remained lower with treatment. Tissue analysis showed decreased staining for PCNA and TUNEL, demonstrating reduced apoptosis. Tubular damage and casts were reduced by 50% with CB2 agonist treatment.

Acute kidney injury is a major problem in hospitalized patients, especially those undergoing cardiac surgery requiring cardiopulmonary bypass. Any agent that shows this much promise deserves further study, even if it won't give you the munchies!

Click author name above for full abstract.


#ExpBio - The Problem with Spinach

Spinach and other dark, leafy greens can bomb the human body with oxalate, a major causative factor for kidney stones. Stones also predict chronic kidney disease, making them more than an inconvenient pain. Spinach smoothie

Mitchell et al, Urologists from the University of Alabama-Birmingham, have found that patients with recurrent oxalate kidney stones show impaired monocyte mitochondrial dysfunction in response to stress in vitro. The present study examined this phenomenon in healthy subjects 21 to 31 years of age with no prior history of stones. Blood for monocyte isolation and oxalate levels was drawn before and 5 hours after an oxalate load delivered as a spinach smoothie.

As expected, blood and urine oxalate increased after the spinach smoothie. Overall, mitochondrial function decreased after oxalate loading, with ~60% of participants showing responses similar to the stone-forming population. The remaining participants had preserved monocyte mitochondrial function.

So oxalate may impair monocyte function in people. Could the 60% with abnormal responses represent future stone-formers? Are these the ones more predisposed to chronic kidney disease after stones? Only time will tell.

In the meantime, I plan to avoid green smoothies on principle. And disgust...lots of disgust.

For abstract, click link on author names above.


#ExpBio - Counterintuitive Results from Framingham

Apr 25 2017 Published by whizbang under [Biology&Environment], [Medicine&Pharma], ExpBio 2017 Framingham is the small city that researchers will not leave alone. We are now into the Framingham Offspring Study, examining relationships between some dietary factors and blood pressure control. The study population included 2632 individuals 30-64 years of age who were not on blood pressure medication at the start of the 16 years of follow-up. In the first 5 years of the study, all kept a 6-day diet diary which was used to estimate daily intake of sodium, potassium, magnesium, and calcium. All analysis corrected for age, gender, smoking, activity level and the other usual suspects.

Results were similar for systolic and diastolic blood pressures, so I will just show systolic here: Systolic blood pressure according to sodium intake among individuals not taking blood pressure lowering medication. Results were adjusted for sex, age, education, height, weight, physical activity, cigarettes per day and alcohol intake.
Credit: Lynn L. Moore, Boston University School of Medicine

How can that be? We have advised healthy individuals to lower salt intake forever to avoid hypertension, yet these folks make that look like exactly the wrong advice. Could there be a confounding diet variable? Let's throw potassium into the mix: Systolic blood pressure according to the combined intakes of sodium and potassium among individuals not taking blood pressure lowering medication. Results were adjusted for sex, age, education, height, weight, physical activity, cigarettes per day and alcohol intake.

So low sodium, with or without high potassium intake, produced higher blood pressures than higher sodium plus high potassium intake. Similar results were found for intake of calcium and magnesium, other ions in the diet that seem to ameliorate hypertension.

There are some caveats here, like with every research study. First, even though this is a large, longitudinal study, these are people who are second or third generation research subjects. Being in cardiovascular research likely makes them more health conscious, so their level of sodium intake may not reflect the general US population. Also, these are healthy, non-hypertensive people. Findings might be quite different in people with high blood pressure or salt-sensitivity. They also have no biomarkers of intake; all diet data is from a 6-day diet diary in the initial years of the study. How eating patterns may have changed over time is just not known. Citizens of Framingham get the same health news as the rest of us; did many start green juicing or go paleo?

This study does bring into question reducing sodium intake for the general population. Those of us with hypertension probably need it, but it may not be important for the majority of people. Intake of other minerals may be far more important for general health (check this post out for more on the interrelationships between Na and K transporters in the kidney).

The bottom line? We should all eat a varied diet, avoiding junk food and focusing on fruits, veggies, and dairy with lean protein sources. That DASH-type diet has been shown to reduce weight and blood pressure.


#ExpBio - It's a Nose, It's a Tongue, It's a Kidney!

For several years I have blogged about the kidney "smelling" stuff. Shepard and Pluznick have now updated their work on kidney olfactory receptor 1393 and it's role in diabetic nephropathy. In mice with this receptor knocked-out, Sglt1 is reduced in the proximal tubular lumen, This results in glycosuria with improvement in glucose tolerance. They then took these mice and fed them a high fat diet. Even with the development of obesity, the knock-out mice maintained better glucose tolerance and did not develop an elevated glomerular filtration rate as wild-type counterparts did. Insulin tolerance was similar between the groups. Mice lacking the olfactory receptor also accumulated less fat in the liver than their wild-type brethren, even though body weights were similar.

There's still more to learn from these animals, but this is exciting work for sure!

This year, we also learned that kidneys can taste! Sweet receptors have been found in the pancreas and other areas of the gut beyond the tongue. They can regulate function of these organs in response to sugars and artificial sweeteners. Kassem, Ares, and Ortiz now show that sweet receptors T1R2/T1R3 are present in the kidney! They localize to the thick ascending limb and increase the presence of NKCC2 on the surface in response to fructose feeding. Gumarin, an antagonist of the receptor, blocks this response to fructose. The knock-out mouse for this sweet receptor shows diminished levels of NKCC2 in the tubular surface; these mice also have increased urine output with decreased osmolality, consistent with diminished efficiency of loop function.

The study only addressed effects of fructose, but given interactions of artificial sweeteners in the gut, there will be a lot more exciting information coming up, I'm sure.

The kidney: it tastes, it smells, it pees. Makes you think twice about eating that asparagus, huh?

Abstracts linked to author names above.


#ExpBio - Oh, K!

I live tweeted this lecture, so the post is my Storify. Got a bit lost during the talk in a string of critical phosphorylations midway through. If you want to know that much about the topic, go read Welling's work!


#ExpBio - Short Term Diet Restrictions for Obesity

Apr 24 2017 Published by whizbang under [Biology&Environment], ExpBio 2017

Obesity and its complications raise major challenges for US healthcare, so better understanding its pathophysiology may help a great many people. Traditional caloric restriction has poor long-term outcomes because very few people can stick to dietary limitations forever. Other approaches have similar problems. Click for image source

This group from the University of Wisconsin took a new tactic with short-term restriction of a single nutrient. Methionine is an amino acid that has high levels in beans, nuts, beef, turkey, pork, fish, eggs, and dairy. The study started with 6-week-old mice fed a high-fat western diet for ten weeks to induce obesity, hepatosteatosis, and hyperglycemia. Some mice continued on this diet, while others received an isocaloric high fat diet without methionine for 5 weeks.

At the end of that time, mice with methionine restriction showed decreased body weight, decreased body fat, less fat in the liver, and improved blood sugars. They looked more like mice on standard chow than high-fat fed mice. Remarkable, considering they were still getting a high-fat diet!

Would this work in people? I don't know if I could do a stringent methionine restriction for a month; look at that food list in the second paragraph! Other strategies might be in order, like swearing off this amino acid one or two days each week or month.

As always, only more research will tell us what might work!

Abstract here.


#ExpBio - Why Do We Eat THAT?



To Boldly "Go" Where No Man Has Gone Before Guess how this works 

Bull or Not?

Feb 11 2013 Published by Pascale Lane under [Biology&Environment]

One of my favorite blogs, The Beauty Brains, posted an answer to the following question recently:

I remember reading on the webs that bull semen was the new thing to make your hair healthy looking and shiny I was wondering if that could actually work?

Seriously? I had not heard this one, and I read fashion mags every morning while I dry my hair! Google to the rescue. Turns out bull semen has been used in salon and spa hair treatments for several years, most often in combination with keratin and other "natural" substances.

The Beauty Brains have training as cosmetic scientists and provided the following answer:

Anyway, as everyone knows bull semen consists of a variety of lipoproteins and nucleic acids, the most predominant being glutamic acid. Given it’s rather…sticky…texture, bull semen will coat the hair and provide some residual shine as long as it’s not washed out.  However, since hair consists of dead cells this amino acid mixture won’t provide any special rejuvenating effect. And, it certainly won’t work as well as an ingredient like silicone. Considering that better alternatives exist, and given the potential sourcing issues involved with obtaining semen, I think I’ll stick to a good shine spray.

You really should click over and read their stuff, especially the puns rejected for the bull semen post.

Of course, I wondered more about this product. Having lived my life in cattle country, I had wandered past a number of exhibits for frozen bull jiz at various state fairs. Artificial insemination is wide-spread in the US:

A large majority of dairy cows in the US, Canada and European countries are artificially inseminated. Artificial insemination of beef cows is also popular, particularly in purebred herds. The advantage of AI over natural service is that it facilitates rapid genetic improvement by allowing use of only the top bulls. Some bulls have sired more than 100,000 offspring via AI.

"Natural service," tee-hee ;). Semen collection involves a cow to get the bull in the mood and an artificial vagina with lube. Pictures can be found here of the ultimate fake mounting with diversion of the bull's penis into the artificial vagina. Bulls get to get off 2-3 times a day for 2 or 3 days each week. I suspect that gives both the bull and the bull-juggler welcome time away from each other.

Here is a video, just in case you are hating your job today:

After collection, technicians examine the semen for quality. Some facilities offer sex-specific samples and other high-end goodies, and all then aliquot and freeze the cattle-cum.

What I have not been able to figure out is what the criteria are for cosmetic use. Do expired or inadequate specimens get shunted to the beauty market? Or do stylists consider avid swimmers necessary for the "beneficial effects?"

I love my current products that contain chemicals concocted in a nice laboratory somewhere, rather than coating my locks with bovine happy juice. That practice just seems wrong, for me and the bull.


#EB2012: Renal Section Honors Di Feng makes an award-winning presentation

Every year the Renal Section of the American Physiological Society grants awards to undergraduate and post-doctoral trainees for work they submit and present at the meeting. A committee selects 5 finalists based on the abstract submitted, and their presentations are judged during the Posters and Professors Session that was held on Sunday, April 22.

Undergraduate Finalists

The award went to Di Feng for her work :

Genetic regulation and functional relevance of the p67phox gene in salt-sensitive hypertension
Di Feng1, Chun Yang1, Jozef Lazar2, David Mattson1, Paul O'Connor1, Allen W. Cowley, Jr. 1,3. 1Physiology Department, 2Human and Molecular Genetics Center, 3Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI Feng receives her plaque while Jacob Richards looks on

A narrow region on rat Chr 13 was identified to harbor salt- sensitive genes. p67phox, a cytosolic subunit of NAD(P)H oxidase, is located in this region. We have previously found that on a high salt diet, the renal outer medulla (OM) of Dahl salt-sensitive (SS) rats exhibited higher levels of p67phox expression and NAD(P)H oxidase activity than salt-resistant congenic rats that contain the p67phox allele from the salt-resistant Brown Norway rat. We generated the first p67phox null mutant (p67phox-/-) SS rat in which we observed significantly reduced salt-sensitive hypertension. In our present study, we sequenced a 1650 bp promoter region and found that the SS allele of p67phox had a 204 bp deletion and four SNPs compared to the BN allele. The activity of the SS p67phox promoter was 1.7 fold higher than that of the BN p67phox promoter. We further characterized p67phox-/- rats and showed that they had a 40% reduction in OM H2O2 levels measured from interstitial fluid collected by microdialysis. Respiratory burst responses of peritoneal macrophages to phorbol 12-myristate 13-acetate were abolished in p67phox-/- rats. p67phox-/- rats also showed reduced renal injury, including reduced OM fibrosis, infiltrated T cells and macrophages, and glomerulosclerosis. These data provide new insights into the genetic regulation and functional relevance of p67phox in salt-sensitive hypertension. (HL-82798; HL-29587)

Postdoctoral finalists included: Dr. Grimm gives me a guided tour of his work

Richard Grimm took home the award for this submission:

SPAK, OSR1 and Cab39/MO25 form an Interdependent Signaling system which Regulates Thiazide-Sensitive Salt- transport, Distal Tubule Mass and Blood Pressure
P Richard Grimm1, Tarvinder Taneja1, Jie Liu1, Richard Coleman1, Yang-Yi Chen1, Eric Delpire2, James B Wade1, Paul A Welling1. 1Physiology, University of Maryland School of Medicine, Baltimore, MD, 2Anesthesiology, Vanderbilt School of Medicine, Nashville, TN

STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) and, Oxidative Stress Related Kinase (OSR1), co-localize at the apical membrane of the Thick ascending Limb (TAL) and Distal Convoluted Tubule (DCT) and both regulate the potassium- dependent sodium-chloride co-transporter, NKCC2, thiazide- sensitive sodium-chloride cotransporter, NCC in vitro. Yet genetic ablation of SPAK in mice causes a salt-wasting nephropathy that is restricted to the DCT, reminiscent of Gitelman’s syndrome. Here, we explore why proper DCT function is especially SPAK- dependent. In the TAL of SPAK-/- mice, OSR1 and Cab39/MO25, a newly described OSR1/SPAK regulatory protein, remain at the apical membrane where they function with a compensatory increase in the AMP-activated kinase (AMPK) to hyper- phosphorylate NKCC2. By contrast, the OSR1/SPAK/M025 signal transduction apparatus is completely disrupted in the DCT. OSR1 and MO25 become largely displaced from the thiazide-sensitive sodium-chloride cotransporter, NCC, and the apical membrane. OSR1 redistributes to dense punctate structures within the cytoplasm. These changes are paralleled by a dramatic decrease in NCC abundance and phosphorylation. Without SPAK and the proper localization of OSR1 and MO25, phosphorylation- dependent regulation of NCC by dietary sodium restriction is lost. SPAK-/- mice also exhibit a decrease in the mass of the distal convoluted tubule, exclusive to DCT1. As a result of the interdependent nature of OSR1 and MO25 on SPAK in the DCT, SPAK-/- mice are highly sensitive to dietary salt-restriction, displaying prolonged negative sodium balance and hypotension. Dr. Grimm wins

